Nerve cells called sympathetic neurons can control the activity of almost all of our organs without any conscious thought on our part. For example, these nerve cells are responsible for accelerating the heart rate during exercise.

In a developing embryo, there are initially more of these neurons than are needed, and only those that develop correctly and form a connection with a target cell will survive. This is because the target cells provide the growing neurons with vital molecules called neurotrophins, which are trafficked back along the nerve fiber and into the main body of the nerve cell to ensure its survival. However, it is largely unknown which proteins or genes are also involved in this developmental process.

Now, Bouilloux, Thireau et al. show that if a gene called Meis1 is inactivated in mice, the sympathetic neurons start to develop and grow nerve fibers, but then fail to establish connections with their target cells and finally die. The Meis1 gene encodes a transcription factor, which is a protein that regulates gene activity. Therefore, Bouilloux, Thireau et al. looked for the genes that are regulated by this transcription factor in sympathetic neurons. This search uncovered several genes that are involved in the packaging and trafficking of molecules within cells.

Other experiments then revealed that the trafficking of molecules back along the nerve fiber was altered in mutant neurons in which the Meis1 gene had been inactivated. Furthermore, Meis1 mutant mice had problems with their heart rate, especially during exercise, and an increased risk of dying from a sudden cardiac arrest.

These findings reveal a transcription factor that helps to establish a connection between a neuron and its target, and that activates a pattern of gene expression that works alongside the neurotrophin-based signals. Since all neurons undergo similar processes during development, future work could ask if comparable patterns of gene expression exist in other types of neurons, and if problems with such processes contribute to some neurodegenerative diseases.

Cardio-vascular diseases and sudden cardiac death (SCD) are together among the highest causes of mortality in the general population, and ventricular arrhythmias are identifiable in almost all cardiac diseases. The incidence of SCD and the poor outcome of sudden cardiac arrest make heart diseases a leading cause of mortality in young individuals (Meyer et al., 2012). Among frequent causes of SCD, numerous genetic mutations have been identified as responsible for arrhythmogenic cardiomyopathies, cardiac malformations or sympatho-vagal dysfunctions (Basso et al., 2012; Chopra and Knollmann, 2011; Fukuda et al., 2015). Congenital cardiac innervation defects or dysfunction are largely implicated in SCD and often involve molecules that are essential for the developmental guidance and axonal growth of cardiac sympathetic nerves, such as Sema3a and Ngf (Dae et al., 1997; Fukuda et al., 2015). Recently, two independent genome wide association studies based on abnormal cardiac conduction as an increased susceptibility to SCD have emphasized a restricted number of genes among which Meis1 (Pfeufer et al., 2010; Smith et al., 2011). Meis1 is a transcription factor of the TALE homeobox gene family, known to play important roles during embryonic development, cardiogenesis and postnatal cardiomyocytes turnover (Moens and Selleri, 2006; Stankunas et al., 2008; Mahmoud et al., 2013).

The early steps of sympathetic neurons development have been extensively documented. During sympathetic neurons formation, a concerted cross-regulated transcriptional network induced by BMPs and involving among others the transcription factors Hand2, Ascl1, Phox2b and Gata3 initially instructs neural crest cells to a sympathetic fate and a noradrenergic phenotype by up-regulating the expressions of general neuronal markers and the monoamines biosynthesis enzymes tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) (Rohrer, 2011). Subsequently, connecting sympathetic neurons with their peripheral target relies on combined actions of locally secreted ligands of various families of trophic factors (Glebova and Ginty, 2005; Ernsberger, 2008; 2009). Artn, a growth factor of the Gdnf family of ligands, acting on GFRα3 and Ret, and the neurotrophin Ntf3 are initially involved in proximal axonal growth, and members of the endothelin family serve as vascular-derived guidance cues for sympathetic neurons (Andres et al., 2001; Enomoto et al., 2001; Honma et al., 2002; Kuruvilla et al., 2004; Makita et al., 2008; Manousiouthakis et al., 2014), allowing sympathetic axons to reach the vicinity of target organs. At later stages, distal axonal growth and target-field innervation are under the control of retrograde Ntrk1/Ngf signaling for most organs including the heart (Glebova and Ginty, 2004). Ngf is secreted in limiting amounts by target organs and binds the high affinity receptor Ntrk1 to induce its phosphorylation and internalization both by clathrin-dependent and independent mechanisms. Retrogradely transported Ngf/Ntrk1 is mediated by Rab5-positive endosomes. This signaling induces phosphorylation of CREB and allows the maintenance of Ntrk1 expression both of which are required to promote axonal growth and branching of sympathetic neurons within their peripheral target organs, and to protect them from naturally occurring cell death (Crowley et al., 1994; Smeyne et al., 1994; Riccio et al., 1997,, 1999; Kuruvilla et al., 2000; MacInnis et al., 2003; Ye et al., 2003; Kuruvilla et al., 2004; Valdez et al., 2005; Harrington et al., 2011; Suo et al., 2014). Whereas part of the transcriptional program regulating the induction of Ntrk1 expression has been revealed in the peripheral nervous system (PNS) through analysis of the effects of Klf7 inactivation (Lei et al., 2005), the transcriptional regulation of molecules implicated in retrograde Ngf/Ntrk1 transport mechanisms in particular or endosomal transport in general are unknown.

We aimed in our study at investigating if Meis1 participates in neural aspects of cardiac regulation by intervening in the differentiation of sympathetic neurons and how Meis1 mutations could mediate susceptibility for unexplained SCD.

In this work, we highlight that loss of Meis1 function in early sympathetic neurons leads to an imbalanced sympatho-vagal regulation of cardiac functions in adult mice resulting in increased susceptibility to SCD. We further demonstrate that this imbalance results from neurodevelopmental defects leading to sympathetic neurons apoptosis and we position Meis1 as novel actor in sympathetic neurons differentiation by its role in distal target-field innervation. Among the target genes regulated by Meis1, we evidenced a transcriptional regulation of proteins necessary for retrograde transport, endosomes formation, functioning and traffic. Accordingly, following specific inactivation of Meis1 in peripheral neurons, the traffic of Rab5⁺ early endosomes is impaired and sympathetic target-field innervation is compromised.

In this work, we demonstrated that genetic inactivation of Meis1 in rodent results in an imbalanced sympatho-vagal regulation of heart functions leading to conduction defects, chronotropic incompetence and premature SCD. In addition, we demonstrated that Meis1 acts independently of the well-studied network of transcription factors governing early specification of sympathetic neurons to orchestrate later phases of neuronal differentiation. Its inactivation results in defects of distal innervation and progressive neuronal apoptosis. Identification of Meis1 effector genes revealed a large number of genes involved in endosomal and clathrin-coated cargoes formation and fusion, as well as cytoskeletal proteins participating in their anchoring and transport. Accordingly, loss of Meis1 function impairs Rab5⁺ endosomes formation and trafficking.

The multilevel origin in the trigger, the persistence and the termination of a variety of inherited arrhythmias such as long QT syndrome, Brugada syndrome, progressive cardiac conduction block, sinus node dysfunction, catecholaminergic polymorphic ventricular tachycardia or sudden infant death syndrome is well established (Keating and Sanguinetti, 2001), and include an imbalanced autonomic regulation. For instance, studies in mice and humans have revealed the implication of Sema3a-mediated sympathetic axonal guidance and patterning in the development of ventricular tachycardia and SCD (Ieda et al., 2007; Nakano et al., 2013; Fukuda et al., 2015). Here, we demonstrated that Meis1 inactivation results at adult stages in a persistent and spontaneous bradycardia, blocks of conduction and severe sinus arrests independently of any cardiac malformation. The situation irreversibly deteriorated in conditions requiring sympathetic activation to restore cardiac homeostasis such as drug administration or the recuperation period following physical activity, thus demonstrating the complete chronotropic incompetence of these mice. In humans, such chronic heart rate abnormalities are associated with the lethal dysrhythmias observed in athletes (Link et al., 2002). Similarly, for infant SCD in which the autonomic regulation is compromised, severe hypoxia or anoxia during sleep lead to lethal bradycardia because autoresuscitation, also known as the Lazarus phenomenon, cannot be initiated to restore heart rate, blood pressure and breathing (Stramba-Badiale et al., 1992; Yun and Lee, 2004). Thus, a failure in sympathetic activation during this phase leads to unexpected and sudden death. Such an increased risk of SCD following exercise and during sleep has also been reported in dogs with inherited spontaneous cardiac arrhythmia (Dae et al., 1997). Similar to our results, in these dogs, the sympathetic innervation is defective. A previous study on E14.5 Meis1^-/- embryos has revealed ventricular septal defect and an overriding aorta in both right and left ventricles (Stankunas et al., 2008). In our study, PLAT^CRE::Meis1^LoxP/LoxP embryos did not present such gross structural defects as evidenced by histologic and echocardiographic measure of several parameters. Observation of the septum in the long and short axis and functional evaluation of the outflow did not reveal any differences between WT and PLAT^CRE::Meis1^LoxP/LoxP mice. In particular, a defect in the septum of adult PLAT^CRE::Meis1^LoxP/LoxP mice would have resulted in dissimilar measures of systolic and diastolic performances due to hemodynamic and rigidity variations. Nevertheless, a septal defect was present when the Meis1^LoxP/LoxP strain was crossed with another strain well-known to recombine in neural crest derivatives, the Wnt1^CRE  strain, confirming the previously reported function of Meis1 in cardiac neural crest (Stankunas et al., 2008). This difference could be due to an earlier expression of the CRE recombinase when driven by the Wnt1 promoter compared to the PLAT. Another explanation could be a lower recombination efficiency of the PLAT^CRE strain specifically in the cardiac neural crest lineage. We conclude that gross morphological alterations similar to those previously reported (Stankunas et al., 2008) do not contribute to the phenotype reported here.

Our results further complement the study by Mahmoud et al. demonstrating Meis1 function in the regulation of neonatal cardiomyocytes mitosis especially following myocardial infarction (Mahmoud et al., 2013). However, cardiac functions were not affected following specific Meis1 inactivation or overexpression in cardiomyocytes (Mahmoud et al., 2013). Finally, because the Meis family participates in cardiogenesis (Stankunas et al., 2008; Mahmoud et al., 2013) and has been associated with SCD by independent GWA studies (Pfeufer et al., 2010; Smith et al., 2011), it is tempting to speculate that Meis1 mutations in humans would result in heart dysfunctions due to cardiac malformations and/or regeneration, sympatho-vagal deregulation of cardiac rhythmicity, or a combination of dysfunctions affecting both compartments.

The onset of Meis1 expression after the early noradrenergic specification transcription factors and noradrenergic markers together with the unaltered expression of Gata3, Phox2b, Hand2 and TH at E14.5 following Meis1 inactivation demonstrated that Meis1 acts independently of the pathways regulating early sympathetic neurons specification. Accordingly, Phox2b expression remained unchanged at later embryonic stages and at P0 in a double Meis1::Bax null context. These findings were confirmed by the normal formation of the sympathetic ganglia up to E14.5 in Meis1 mutants, whereas in Ascl1, Phox2b, Hand2 or Gata3 null mutants, early sympathetic neurons lose TH and DBH expression, fail to proliferate and to coalesce in a ganglion and precociously die upon arrival in the sympathetic anlage (Rohrer, 2011).

In Drosophila, inactivation of Homothorax (Hth), the ortholog of Meis1, leads to neuronal and dendritic patterning defect in the PNS (Kurant et al., 1998; Ando et al., 2011; Baek et al., 2013). Hth is also required for survival of a subset of postmitotic motoneurons and rescuing them from apoptosis demonstrated that Hth shapes axons and dendrites by regulating a set of target genes independently of Hox functions (Baek et al., 2013). However, the precise mechanism and the transcriptional targets by which Hth mediates these effects have not been elucidated. We propose that the regulation of the expression of genes involved in early endosomes formation and transport by Meis1 is a means of coordinating target-field innervation and survival. Accordingly, our identification of Meis1 effector genes highlighted numerous key genes for vesicles formation, fusion and transport, thus providing support for a coordinated action of Meis1 in retrograde dependent target-field innervation and neuronal survival.

The transcriptional program we identified by ChIP-seq is in broad agreement with ChIP-seq performed by others on other tissues (Wilson et al., 2010; Penkov et al., 2013). In a ChIP-seq performed on E11.5 trunk mouse embryos, ontology analysis of potential Meis1 target genes identified among the most enriched Meis1 bound sequences, genes involved in nervous system development, axonal guidance and synapse organization (Penkov et al., 2013). More surprisingly, comparison of our ChIP-seq results with results of a ChIP-seq conducted on a hematopoietic progenitor cell line revealed 37% of common potential targets between these two tissues (Wilson et al., 2010). Strikingly, these shared genes represent 41, 56, 75 and 50% of the genes we classified as involved in synaptic machinery, in clathrin/dynein complexes, in microtubule-associated axonal growth and in the regulation of endocytosis respectively (Figure 6—source data 3). From our ChIP-seq analysis, we independently confirmed that the expression of Syt1, Lnp, Adam19, Nbea and Dst mRNAs is modified. Although endosomal structures present a high diversity in their shapes and molecular compositions depending on the process they participate in, they also share a number of proteins assuming similar roles. Syt1 is an example of protein present in most, if not all, vesicular types where it acts as calcium sensor for exocytosis and endocytosis (Kraszewski et al., 1995; Takei and Haucke, 2001; Rizo and Rosenmund, 2008). Syt1 serves, just like synaptophysin, as a high affinity receptor at the plasma membrane of nerves-endings for clathrin AP-2, therefore participating in clathrin coated-pit nucleation and endocytosis (Zhang et al., 1994; Haucke and De Camilli, 1999). Syt1 also promotes axonal filopodia formation and branching in fibroblasts and embryonic chick forebrain neurons in culture (Feany and Buckley, 1993; Greif et al., 2013). We therefore conclude that at least part of the transcriptional program governed by Meis1 influences endocytosis and retrograde transport. In line with this, we demonstrated in E16.5 embryos, a time when retrograde transport is critical for neuronal survival and target-field innervation, that clathrin immunoreactivity is virtually absent from Meis1 inactivated sympathetic neurons. In sympathetic neurons growing from cultured SCGs explants, the numbers of Rab5⁺, Syp1⁺ and clathrin⁺ cargoes were also reduced, and overexpressing Rab5 was unable to rescue the number of Rab5⁺ endosomes. In addition, time-lapse analysis demonstrated profound alterations in the traffic and velocity of the remaining Rab5⁺ endosomes, and TEM analysis showed that within sympathetic axons from mutant embryos the number as well as the surface area occupied by endocytic figures is reduced. We thus conclude that the transcriptional program initiated by Meis1 interferes with the retrograde transport of trophic factors as was hypothesized for Hth in Drosophila motor neurons (Baek et al., 2013).

Because many organelles and various kind of vesicles use similar transport machinery, the loss of expression of universal components such as Syt1, Syp1, Clathrin and Rab5 raises the possibility that other mechanisms than Ngf/Ntrk1 retrograde transport are affected. Indeed, our result are consistent with a function of Meis1 interfering with the retrograde transport of several trophic factors.

In our study, we detected an increased apoptosis of Meis1 inactivated sympathetic neurons at E14.5 that did not result in a significant variation in the volume of the SCGs, and at E16.5 concomitantly with a significant reduction in the volume of the mutant SCGs. By E18.5, the volume of the mutant SCGs was massively reduced. Whereas the increased apoptosis at E16.5 and the further dramatic decrease of SCG volume at E18.5 coincides with the period of retrograde-signal mediating target-field innervation and survival, early apoptosis at E14.5 does not. Similarly, because in Ngf knockout mice, the defects in distal sympathetic innervation does not affect the trachea (Glebova and Ginty, 2004), we tentatively conclude that Meis1 inactivation not only impairs Ngf/Ntrk1 retrograde signaling but also other retrograde signals important for survival. Among potential retrograde signaling pathways influencing sympathetic neurons survival, members of the Gdnf family of ligands and their receptors play important functions. They participate in various aspects of embryonic sympathetic development including precursors migration, proliferation, axonal growth and neurons survival (Ernsberger, 2008). Early sympathetic neurons (E12) express Ret, GFRα1, 2 and 3 (Nishino et al., 1999). Artn serves as an intermediate target derived trophic factor for sympathetic neurons (Honma et al., 2002). In vitro, it influences the proliferation of neuroblasts from E12 to E14 and exerts a transient survival effect on newly generated neurons during this period (Andres et al., 2001). In agreement, in GFRα3 KO the proliferation of neuroblasts is affected (Andres et al., 2001), but inactivation of Artn or GRFα3 does not induce apoptosis at E14.5 (Honma et al., 2002). In Ret mutants, SCGs are mislocated and axonal growth defects are found starting E10.5 to E13 (Enomoto et al., 2001). However, no increase in Casp3 staining was found before E16.5 and apoptosis is enhanced only perinataly (Enomoto et al., 2001). In Gdnf mutants, there is a 35% reduction in the number of SCG neurons at P0 but earlier embryonic stages have not been investigated (Moore et al., 1996). However, in vitro, Gdnf promotes the survival of 30% of E13.5 rat sympathetic neurons (Heermann et al., 2013). Whether Gdnf can be retrogradely transported by sympathetic neurons remains controversial. Studies in neonatal and adult sympathetic indicate that Gdnf is not a retrograde survival factor (Leitner et al., 1999; Tsui and Pierchala, 2010), whereas others reported in rat embryonic neurons that application of Gdnf to the distal compartment induces axonal growth and survival via a retrograde signaling involving GFRα1 (Coulpier and Ibáñez, 2004). The expression of Gdnf and Artn in various intermediate and/or final target organs of sympathetic neurons during development (Buj-Bello et al., 1995; Ebendal et al., 1995; Honma et al., 2002; Miwa et al., 2010) suggests that these factors may be retrogradely transported at least during the embryonic period. It is also possible that other yet unidentified factors use retrograde transport to mediate target-field innervation and survival. We conclude that the dramatic decrease in the number of sympathetic neurons we observed at E18.5 and the general defect in target organs innervation are likely to result from impaired retrograde signaling of more than one trophic factor. Among them, because of its well-established function in target-field innervation and survival, we focused our study on retrograde Ngf/Ntrk1 downstream signaling as a proof of impaired retrograde signaling. In addition, the molecular relation between Rab5⁺ endosomes and neurotrophins retrograde signaling including retrograde Ntrk1/Ngf signaling has been extensively documented (Deinhardt et al., 2006,, 2007; Varsano et al., 2006; Cui et al., 2007; Liu et al., 2007; Valdez et al., 2007; Philippidou et al., 2011). Indeed, downstream readout of Ngf/Ntrk1 retrograde signaling i.e. the nuclear expression of phosphorylated CREB (Riccio et al., 1997) and the level of Ntrk1 expression confirmed an impairment of Ngf/Ntrk1 retrograde signaling. This is supported by the decreased number of pCREB⁺ neurons at E14.5 when the first small subset of Ngf responsive sympathetic neurons are observed (Coughlin and Collins, 1985; Korsching and Thoenen, 1988), and the decreased nuclear expression of pCREB at E16.5 when survival of most sympathetic neurons depends on retrograde Ngf/Ntrk1 signaling (Glebova and Ginty, 2004; Kuruvilla et al., 2004). Similarly, because in sympathetic neurons the maintenance of Ntrk1 expression depends on retrogradely transported Ngf and because Klf7 is regulated by Ngf (Deppmann et al., 2008), the down regulation of Ntrk1, and possibly Klf7 we report in Meis1 mutant is likely to be a consequence of impaired retrograde signaling of this neurotrophin. However, although the participation of Ngf/Ntrk1 retrograde signaling in the neuronal loss observed after E16.5 is supported by the loss of Ntrk1 expression and by the rescue of Meis1 inactivated sympathetic neurons in a null Bax context at P0, we have no direct evidence of an Ngf dependent apoptosis. In line with this, although it was initially proposed that the survival effect of retrograde Ngf/Ntrk1 signaling was mediated through CREB activation (Riccio et al., 1999; Lonze et al., 2002), specific inactivation of CREB in sympathetic neurons protects against developmentally regulated apoptosis (Parlato et al., 2007). Thus, the decrease in pCREB expression in Meis1 mutant cannot explain the neuronal loss.

The increased apoptosis at E14.5 remains more intriguing. It involves about 5% of TH-positive cells in the SCGs and does not result in a significant volume decrease of the mutant SCGs at this stage. In other mutant mice, apoptosis at this stage has been reported (Maina et al., 1998; Armstrong et al., 2011). For instance, Met is expressed in SCG from E12.5 embryo (Maina et al., 1998) and blocking of HGF signaling or Met inactivation prevent early sympathetic neuroblasts differentiation into neurons from E12.5 to E14.5 without affecting their proliferation. During this period of development, HGF/Met favors the survival of sympathetic neuroblasts and in Met mutants apoptosis is increased at E14.5 (Maina et al., 1998). In Fz3 mutants, apoptosis is increased at E13.5 and E14.5 in sympathetic neuroblasts but cannot be rescued by Bax elimination (Armstrong et al., 2011). It is thus possible that Meis1 influences the survival of a small subset of sympathetic neuroblasts by interfering with one of the above pathways. Another explanation could be that a small subset of neurons depends on the retrograde transport of a trophic factor other than Ntrk1 at this stage. This hypothesis is consistent with the lack of induction of Syt1 expression at E14.5 whereas the induction of Ntrk1 expression is unaffected. Finally, our ChIP-seq experiment identified several potential target genes known to be involved in axonal growth and/or guidance (about 20%) as well as many other genes which function has not been yet studied. Thus, we cannot exclude that a deregulation of the expression of some of these genes is responsible for the apoptosis in this small subset of neurons. For instance, Gdnf was identified as a potential target gene in this search. Since the function of Gdnf on survival of early SCG neurons remains unclear, and because some studies detected Gdnf mRNA in embryonic sympathetic neurons (Trupp et al., 1995), a potential regulation of its expression by Meis1 could account for the increased apoptosis of this small subset of neurons.

To conclude, our results show that Meis1 inactivation induces apoptosis of embryonic sympathetic neurons through different mechanisms: a severe loss of neurons occurring after E16.5 in which impaired retrograde trafficking of Ngf/Ntrk1 is a contributing factor together with other target-derived trophic factors, and a weaker apoptosis from E14.5 to E16.5 that is independent of Ngf/Ntrk1 retrograde signaling.

How Meis1 is regulated in sympathetic neurons? In our study, we showed that Meis1 is not regulated by Ngf. In several neuronal and non-neuronal tissues, Meis1 expression is differentially modulated by retinoic acid (RA) and bFGF. Mouse embryos treated with high doses of RA show increased levels of Meis1 (Qin et al., 2002) and in the chick limb bud, RA induces Meis1 expression whereas bFGF reduces it (Mercader et al., 2000). During development of striatonigral projection neurons, retinoic acid and FGF are required for positioning the boundaries of Meis1-expressing cells (Rataj-Baniowska et al., 2015). Thus, when RARβ is inactivated, the number of Meis1 positive cells is increased and this effect can be reversed by addition of FGF2 (Rataj-Baniowska et al., 2015). Meis1 expression is also induced in differentiated forebrain-derived neural stem cells in the presence of bFGF (Barber et al., 2013). In P19 and F9 carcinoma cells and in the U937 human leukemic monocyte lymphoma cell line, RA treatment rapidly induces Meis1 expression (Ferretti et al., 2000; Longobardi and Blasi, 2003; Meester-Smoor et al., 2008). In RA-treated human carcinoma cell line NT2/D1, a treatment that induces neuronal terminal differentiation, Meis1 is also up regulated (Freemantle et al., 2002). In agreement with a potential regulation of Meis1 expression by RA during sympathetic neurons development, all RA receptors RARα, RARβ, RARγ and RXR are dynamically expressed (Plum and Clagett-Dame, 1996; Doxakis and Davies, 2005).

The role of RA in neurogenesis, axonal growth and maintenance of differentiated neurons is well known and relies on complex mechanisms depending on RA receptors expression, RA concentration, cellular context and time-exposure, (Clagett-Dame and Plum, 1997; Maden, 2007). The complexity of RA signaling is outlined by the various effects reported depending on embryonic stages and the species analyzed with sometimes conflicting results. In chick, a role of RA in sympathetic target field-innervation and neurons survival has been suggested (Rodriguez-Tébar and Rohrer, 1991; von Holst et al., 1995; Plum and Clagett-Dame, 1996; Repa et al., 1996; Reis et al., 2002). RA induces Ntrk1 expression and regulates the onset of Ngf dependence (Rodriguez-Tébar and Rohrer, 1991; von Holst et al., 1995; Plum et al., 2001). In chick, the expression of the other neurotrophins receptors is not modified by RA (von Holst et al., 1995), although RA also potentiates the survival and neurite outgrowth induced by Ntf3 (Plum et al., 2001) likely through Ntrk1 activation. At later stages, RA also reduces the survival effect of Gdnf and Neurturin of chick sympathetic neurons by preventing GFRα1, GFRα2 and Ret expression (Doxakis and Davies, 2005).

In rodents, the scenario seems different. RA treatment of mouse and rat sympathetic neurons prevents Ntrk1 mRNA developmental induction and increases Ntrk3, Ntrk2 and Ngfr mRNA expression (Kobayashi et al., 1994; Wyatt et al., 1999). Contrary to chick, RA enhances Gdnf and Ntf3 responsiveness of cultured rat sympathetic neurons (Thang et al., 2000). Interestingly, RA induces the expression of several synaptic vesicles proteins including SYT1 in human neural stem cell (Ekici et al., 2008). Less is known about the function of FGFs in early sympathetic neurons. FGF8 is expressed in E14.5 mouse sympathetic neurons (Tanaka et al., 2001), and FGF2 and FGFR1 are expressed in rat postmitotic sympathetic neurons (Nindl et al., 2004). bFGF induces a sympathetic neuron phenotype on PC12 cells and promotes neurite outgrowth and survival (Rydel and Greene, 1987). In chromaffin cells, it induces a dependence on Ngf for survival (Stemple et al., 1988). Thus, it seems that during sympathetic neurons development, RA and FGFs regulate the responsiveness of sympathetic neurons to multiple neurotrophic factors, which is in agreement with the function of Meis1 we propose. If such a regulation exists, it could be hypothesized that Meis1 is necessary to ensure the transition from local to target-derived neurotrophic signaling.

Two classes of transcription factors involved in late neuronal differentiation have been recently defined: terminal selector genes and dedicated maintenance factors (Hobert, 2008; Hobert et al., 2010; Hobert, 2011; Deneris and Hobert, 2014; Allan and Thor, 2015). Terminal selector genes group transcriptional regulators of effector genes defining a unique identity trait for a given subtype of neuron. Their removal results in the loss of many functionally unrelated terminal identity features such as neurotransmitter identity, neurotransmitter receptors, ion channels, whereas features shared by all neurons such as expression of synaptic vesicle proteins are unaffected (Deneris and Hobert, 2014). Dedicated maintenance transcription factors include genes whose expression commences after neuron-type identity is acquired and that are not involved in initial specification (Deneris and Hobert, 2014). Rather, they are necessary for maintenance of neuronal identity and survival. Terminal selector genes for sympathetic neurons unambiguously include Phox2b, Gata3 and Hand2 which the most studied function is to control the expression of TH and DBH, two key enzymes involved in the noradrenergic identity (Rohrer, 2011). Thus, according to these definitions and from our results, Meis1 belongs to the second class of dedicated maintenance factors. A well-studied example of such factors is the Engrailed (Eng) family. In Eng1/2 double mutants, mesencephalic dopaminergic neurons are generated and specified normally before being progressively eliminated by apoptosis (Simon et al., 2001, , 2004; Albéri et al., 2004; ; Sgado et al., 2006). In vitro, proximal axonal growth in double Eng1/2 mutant is unaffected whereas in vivo, the projections of these neurons toward the basal telencephalon are missing. Interestingly, in Eng1/Eng2 double mutants, neuronal apoptosis is preceded by a loss of α-synuclein expression (Simon et al., 2001), a vesicular protein able to modulate clathrin-dependent endocytosis, vesicle trafficking and recycling (Kuwahara et al., 2008; Ben Gedalya et al., 2009; Nemani et al., 2010; Cheng et al., 2011; Kisos et al., 2014; Vargas et al., 2014). Thus, the neuronal phenotypes we report following Meis1 inactivation strikingly resemble the phenotypes reported for Eng mutation in mesencephalic dopaminergic neurons. Whether the regulation of generic traits for all neurons is a common feature of this class of dedicated maintenance factors remain to be explored.

Finally, it has been proposed that disruption of transcriptional maintenance programs is a key to increased susceptibility to late onset neurodegenerative disease (Deneris and Hobert, 2014). Since Meis1 is expressed by numerous post-mitotic neurons (Toresson et al., 2000), it is likely that the transcriptional program initiated by Meis1 that we reported in sympathetic neurons will be generalized to other class of CNS neurons.

1. 1. Fabrice Bouilloux
   2. Frédéric Marmigère

   (2015) Search for Meis1 target genes in embryonic sympathetic neurons

   Publicly available at the Gene Expression Omnibus (accession no. GSE54144).

   http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54144

1. 1. Akselrod S
   2. Gordon D
   3. Ubel FA
   4. Shannon DC
   5. Berger AC
   6. Cohen RJ

   (1981)

   Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control

   Science  213:220–222.

   • Google Scholar
2. 1. Albéri L
   2. Sgadò P
   3. Simon HH

   (2004) Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons

   Development 131:3229–3236.

   https://doi.org/10.1242/dev.01128

   • Google Scholar
3. 1. Allan DW
   2. Thor S

   (2015) Transcriptional selectors, masters, and combinatorial codes: regulatory principles of neural subtype specification

   Wiley Interdisciplinary Reviews. Developmental Biology 4:505–528.

   https://doi.org/10.1002/wdev.191

   • Google Scholar
4. 1. Ando M
   2. Totani Y
   3. Walldorf U
   4. Furukubo-Tokunaga K

   (2011) TALE-class homeodomain transcription factors, homothorax and extradenticle, control dendritic and axonal targeting of olfactory projection neurons in the drosophila brain

   Developmental Biology 358:122–136.

   https://doi.org/10.1016/j.ydbio.2011.07.018

   • Google Scholar
5. 1. Andres R
   2. Forgie A
   3. Wyatt S
   4. Chen Q
   5. de Sauvage FJ
   6. Davies AM

   (2001)

   Multiple effects of artemin on sympathetic neurone generation, survival and growth

   Development 128:3685–3695.

   • Google Scholar
6. 1. Armstrong A
   2. Ryu YK
   3. Chieco D
   4. Kuruvilla R

   (2011) Frizzled3 is required for neurogenesis and target innervation during sympathetic nervous system development

   The Journal of Neuroscience  31:2371–2381.

   https://doi.org/10.1523/JNEUROSCI.4243-10.2011

   • Google Scholar
7. 1. Baek M
   2. Enriquez J
   3. Mann RS

   (2013) Dual role for hox genes and hox co-factors in conferring leg motoneuron survival and identity in drosophila

   Development  140:2027–2038.

   https://doi.org/10.1242/dev.090902

   • Google Scholar
8. 1. Barber BA
   2. Liyanage VR
   3. Zachariah RM
   4. Olson CO
   5. Bailey MA
   6. Rastegar M

   (2013) Dynamic expression of MEIS1 homeoprotein in E14.5 forebrain and differentiated forebrain-derived neural stem cells

   Annals of Anatomy = Anatomischer Anzeiger  195:431–440.

   https://doi.org/10.1016/j.aanat.2013.04.005

   • Google Scholar
9. 1. Basso C
   2. Bauce B
   3. Corrado D
   4. Thiene G

   (2012) Pathophysiology of arrhythmogenic cardiomyopathy

   Nature Reviews. Cardiology 9:223–233.

   https://doi.org/10.1038/nrcardio.2011.173

   • Google Scholar
10. 1. Ben Gedalya T
    2. Loeb V
    3. Israeli E
    4. Altschuler Y
    5. Selkoe DJ
    6. Sharon R

    (2009) Alpha-synuclein and polyunsaturated fatty acids promote clathrin-mediated endocytosis and synaptic vesicle recycling

    Traffic  10:218–234.

    https://doi.org/10.1111/j.1600-0854.2008.00853.x

    • Google Scholar
11. 1. Berul CI
    2. Maguire CT
    3. Gehrmann J
    4. Reddy S

    (2000)

    Progressive atrioventricular conduction block in a mouse myotonic dystrophy model

    Journal of Interventional Cardiac Electrophysiology  4:351–358.

    • Google Scholar
12. 1. Bourane S
    2. Méchaly I
    3. Venteo S
    4. Garces A
    5. Fichard A
    6. Valmier J
    7. Carroll P

    (2007) A SAGE-based screen for genes expressed in sub-populations of neurons in the mouse dorsal root ganglion

    BMC Neuroscience 8:97.

    https://doi.org/10.1186/1471-2202-8-97

    • Google Scholar
13. 1. Buj-Bello A
    2. Buchman VL
    3. Horton A
    4. Rosenthal A
    5. Davies AM

    (1995)

    GDNF is an age-specific survival factor for sensory and autonomic neurons

    Neuron 15:821–828.

    • Google Scholar
14. 1. Cheng F
    2. Li X
    3. Li Y
    4. Wang C
    5. Wang T
    6. Liu G
    7. Baskys A
    8. Uéda K
    9. Chan P
    10. Yu S

    (2011) α-synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death

    Journal of Neurochemistry 119:815–825.

    https://doi.org/10.1111/j.1471-4159.2011.07460.x

    • Google Scholar
15. 1. Chopra N
    2. Knollmann BC

    (2011) Genetics of sudden cardiac death syndromes

    Current Opinion in Cardiology 26:196–203.

    https://doi.org/10.1097/HCO.0b013e3283459893

    • Google Scholar
16. 1. Choudhary B
    2. Ito Y
    3. Makita T
    4. Sasaki T
    5. Chai Y
    6. Sucov HM

    (2006) Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (tgfbr2) mutant mice

    Developmental Biology 289:420–429.

    https://doi.org/10.1016/j.ydbio.2005.11.008

    • Google Scholar
17. 1. Clagett-Dame M
    2. Plum LA

    (1997)

    Retinoid-regulated gene expression in neural development

    Critical Reviews in Eukaryotic Gene Expression 7:299–342.

    • Google Scholar
18. 1. Coughlin MD
    2. Collins MB

    (1985)

    Nerve growth factor-independent development of embryonic mouse sympathetic neurons in dissociated cell culture

    Developmental Biology 110:392–401.

    • Google Scholar
19. 1. Coulpier M
    2. Ibáñez CF

    (2004) Retrograde propagation of GDNF-mediated signals in sympathetic neurons

    Molecular and Cellular Neurosciences 27:132–139.

    https://doi.org/10.1016/j.mcn.2004.06.001

    • Google Scholar
20. 1. Crowley C
    2. Spencer SD
    3. Nishimura MC
    4. Chen KS
    5. Pitts-Meek S
    6. Armanini MP
    7. Ling LH
    8. McMahon SB
    9. Shelton DL
    10. Levinson AD

    (1994)

    Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons

    Cell 76:1001–1011.

    • Google Scholar
21. 1. Cui B
    2. Wu C
    3. Chen L
    4. Ramirez A
    5. Bearer EL
    6. Li W-P
    7. Mobley WC
    8. Chu S

    (2007) One at a time, live tracking of NGF axonal transport using quantum dots

    Proceedings of the National Academy of Sciences of the United States of America 104:13666–13671.

    https://doi.org/10.1073/pnas.0706192104

    • Google Scholar
22. 1. Dae MW
    2. Lee RJ
    3. Ursell PC
    4. Chin MC
    5. Stillson CA
    6. Moise NS

    (1997)

    Heterogeneous sympathetic innervation in german shepherd dogs with inherited ventricular arrhythmia and sudden cardiac death

    Circulation 96:1337–1342.

    • Google Scholar
23. 1. Danielian PS
    2. Muccino D
    3. Rowitch DH
    4. Michael SK
    5. McMahon AP

    (1998)

    Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of cre recombinase

    Current Biology 8:1323–1326.

    • Google Scholar
24. 1. Deinhardt K
    2. Reversi A
    3. Berninghausen O
    4. Hopkins CR
    5. Schiavo G

    (2007) Neurotrophins redirect p75NTR from a clathrin-independent to a clathrin-dependent endocytic pathway coupled to axonal transport

    Traffic  8:1736–1749.

    https://doi.org/10.1111/j.1600-0854.2007.00645.x

    • Google Scholar
25. 1. Deinhardt K
    2. Salinas S
    3. Verastegui C
    4. Watson R
    5. Worth D
    6. Hanrahan S
    7. Bucci C
    8. Schiavo G

    (2006) Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway

    Neuron 52:293–305.

    https://doi.org/10.1016/j.neuron.2006.08.018

    • Google Scholar
26. 1. Deneris ES
    2. Hobert O

    (2014) Maintenance of postmitotic neuronal cell identity

    Nature Neuroscience 17:899–907.

    https://doi.org/10.1038/nn.3731

    • Google Scholar
27. 1. Deppmann CD
    2. Mihalas S
    3. Sharma N
    4. Lonze BE
    5. Niebur E
    6. Ginty DD

    (2008) A model for neuronal competition during development

    Science  320:369–373.

    https://doi.org/10.1126/science.1152677

    • Google Scholar
28. 1. Doxakis E
    2. Davies AM

    (2005) Retinoic acid negatively regulates GDNF and neurturin receptor expression and responsiveness in embryonic chicken sympathetic neurons

    Molecular and Cellular Neurosciences 29:617–627.

    https://doi.org/10.1016/j.mcn.2005.04.011

    • Google Scholar
29. 1. Ebendal T
    2. Tomac A
    3. Hoffer BJ
    4. Olson L

    (1995) Glial cell line-derived neurotrophic factor stimulates fiber formation and survival in cultured neurons from peripheral autonomic ganglia

    Journal of Neuroscience Research 40:276–284.

    https://doi.org/10.1002/jnr.490400217

    • Google Scholar
30. 1. Edgar R
    2. Domrachev M
    3. Lash AE

    (2002)

    Gene expression omnibus: NCBI gene expression and hybridization array data repository

    Nucleic Acids Research 30:207–210.

    • Google Scholar
31. 1. Ekici M
    2. Hohl M
    3. Schuit F
    4. Martínez-Serrano A
    5. Thiel G

    (2008) Transcription of genes encoding synaptic vesicle proteins in human neural stem cells: chromatin accessibility, histone methylation pattern, and the essential role of rest

    The Journal of Biological Chemistry 283:9257–9268.

    https://doi.org/10.1074/jbc.M709388200

    • Google Scholar
32. 1. Electrophysiology TFotESoCatNASoPa

    (1996)

    Heart rate variability: standards of measurement, physiological interpretation and clinical use. task force of the european society of cardiology and the north american society of pacing and electrophysiology

    Circulation 93:1043–1065.

    • Google Scholar
33. 1. Enomoto H
    2. Crawford PA
    3. Gorodinsky A
    4. Heuckeroth RO
    5. Johnson EM
    6. Milbrandt J

    (2001)

    RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons

    Development  128:3963–3974.

    • Google Scholar
34. 1. Ernsberger U

    (2008) The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons

    Cell and Tissue Research 333:353–371.

    https://doi.org/10.1007/s00441-008-0634-4

    • Google Scholar
35. 1. Ernsberger U

    (2009) Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

    Cell and Tissue Research 336:349–384.

    https://doi.org/10.1007/s00441-009-0784-z

    • Google Scholar
36. 1. Feany MB
    2. Buckley KM

    (1993) The synaptic vesicle protein synaptotagmin promotes formation of filopodia in fibroblasts

    Nature 364:537–540.

    https://doi.org/10.1038/364537a0

    • Google Scholar
37. 1. Ferretti E
    2. Marshall H
    3. Pöpperl H
    4. Maconochie M
    5. Krumlauf R
    6. Blasi F

    (2000)

    Segmental expression of Hoxb2 in r4 requires two separate sites that integrate cooperative interactions between Prep1, pbx and hox proteins

    Development  127:155–166.

    • Google Scholar
38. 1. Freemantle SJ
    2. Kerley JS
    3. Olsen SL
    4. Gross RH
    5. Spinella MJ

    (2002) Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma

    Oncogene 21:2880–2889.

    https://doi.org/10.1038/sj.onc.1205408

    • Google Scholar
39. 1. Fukuda K
    2. Kanazawa H
    3. Aizawa Y
    4. Ardell JL
    5. Shivkumar K

    (2015) Cardiac innervation and sudden cardiac death

    Circulation Research 116:2005–2019.

    https://doi.org/10.1161/CIRCRESAHA.116.304679

    • Google Scholar
40. 1. Gehrmann J
    2. Hammer PE
    3. Maguire CT
    4. Wakimoto H
    5. Triedman JK
    6. Berul CI

    (2000)

    Phenotypic screening for heart rate variability in the mouse

    American Journal of Physiology. Heart and Circulatory Physiology 279:H733–H740.

    • Google Scholar
41. 1. Glebova NO
    2. Ginty DD

    (2004) Heterogeneous requirement of NGF for sympathetic target innervation in vivo

    The Journal of Neuroscience  24:743–751.

    https://doi.org/10.1523/JNEUROSCI.4523-03.2004

    • Google Scholar
42. 1. Glebova NO
    2. Ginty DD

    (2005) Growth and survival signals controlling sympathetic nervous system development

    Annual Review of Neuroscience 28:191–222.

    https://doi.org/10.1146/annurev.neuro.28.061604.135659

    • Google Scholar
43. 1. Greif KF
    2. Asabere N
    3. Lutz GJ
    4. Gallo G

    (2013) Synaptotagmin-1 promotes the formation of axonal filopodia and branches along the developing axons of forebrain neurons

    Developmental Neurobiology 73:27–44.

    https://doi.org/10.1002/dneu.22033

    • Google Scholar
44. 1. Harrington AW
    2. St Hillaire C
    3. Zweifel LS
    4. Glebova NO
    5. Philippidou P
    6. Halegoua S
    7. Ginty DD

    (2011) Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival

    Cell 146:421–434.

    https://doi.org/10.1016/j.cell.2011.07.008

    • Google Scholar
45. 1. Haucke V
    2. De Camilli P

    (1999)

    AP-2 recruitment to synaptotagmin stimulated by tyrosine-based endocytic motifs

    Science  285:1268–1271.

    • Google Scholar
46. 1. Heermann S
    2. Mätlik K
    3. Hinz U
    4. Fey J
    5. Arumae U
    6. Krieglstein K

    (2013) Glia cell line-derived neurotrophic factor mediates survival of murine sympathetic precursors

    Journal of Neuroscience Research 91:780–785.

    https://doi.org/10.1002/jnr.23188

    • Google Scholar
47. 1. Hobert O
    2. Carrera I
    3. Stefanakis N

    (2010) The molecular and gene regulatory signature of a neuron

    Trends in Neurosciences 33:435–445.

    https://doi.org/10.1016/j.tins.2010.05.006

    • Google Scholar
48. 1. Hobert O

    (2008)

    Regulatory logic of neuronal diversity: terminal selector genes and selector motifs

    Proceedings of The National Academy of Sciences of the United States of America 105:20067–20071.

    • Google Scholar
49. 1. Hobert O

    (2011) Regulation of terminal differentiation programs in the nervous system

    Annual Review of Cell and Developmental Biology 27:681–696.

    https://doi.org/10.1146/annurev-cellbio-092910-154226

    • Google Scholar
50. 1. Honma Y
    2. Araki T
    3. Gianino S
    4. Bruce A
    5. Heuckeroth R
    6. Johnson E
    7. Milbrandt J

    (2002)

    Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons

    Neuron 35:267–282.

    • Google Scholar
51. 1. Ieda M
    2. Kanazawa H
    3. Kimura K
    4. Hattori F
    5. Ieda Y
    6. Taniguchi M
    7. Lee JK
    8. Matsumura K
    9. Tomita Y
    10. Miyoshi S
    11. Shimoda K
    12. Makino S
    13. Sano M
    14. Kodama I
    15. Ogawa S
    16. Fukuda K

    (2007) Sema3a maintains normal heart rhythm through sympathetic innervation patterning

    Nature Medicine 13:604–612.

    https://doi.org/10.1038/nm1570

    • Google Scholar
52. 1. Keating MT
    2. Sanguinetti MC

    (2001)

    Molecular and cellular mechanisms of cardiac arrhythmias

    Cell 104:569–580.

    • Google Scholar
53. 1. Kirby ML
    2. Waldo KL

    (1995)

    Neural crest and cardiovascular patterning

    Circulation Research 77:211–215.

    • Google Scholar
54. 1. Kisos H
    2. Ben-Gedalya T
    3. Sharon R

    (2014) The clathrin-dependent localization of dopamine transporter to surface membranes is affected by α-synuclein

    Journal of Molecular Neuroscience 52:167–176.

    https://doi.org/10.1007/s12031-013-0118-1

    • Google Scholar
55. 1. Knudson CM
    2. Tung KS
    3. Tourtellotte WG
    4. Brown GA
    5. Korsmeyer SJ

    (1995)

    Bax-deficient mice with lymphoid hyperplasia and male germ cell death

    Science  270:96–99.

    • Google Scholar
56. 1. Kobayashi M
    2. Kurihara K
    3. Matsuoka I

    (1994)

    Retinoic acid induces BDNF responsiveness of sympathetic neurons by alteration of trk neurotrophin receptor expression

    FEBS Letters 356:60–65.

    • Google Scholar
57. 1. Korsching S
    2. Thoenen H

    (1988)

    Developmental changes of nerve growth factor levels in sympathetic ganglia and their target organs

    Developmental Biology 126:40–46.

    • Google Scholar
58. 1. Kraszewski K
    2. Mundigl O
    3. Daniell L
    4. Verderio C
    5. Matteoli M
    6. De Camilli P

    (1995)

    Synaptic vesicle dynamics in living cultured hippocampal neurons visualized with CY3-conjugated antibodies directed against the lumenal domain of synaptotagmin

    The Journal of Neuroscience  15:4328–4342.

    • Google Scholar
59. 1. Kuhlbrodt K
    2. Herbarth B
    3. Sock E
    4. Hermans-Borgmeyer I
    5. Wegner M

    (1998)

    Sox10, a novel transcriptional modulator in glial cells

    The Journal of Neuroscience  18:237–250.

    • Google Scholar
60. 1. Kurant E
    2. Pai CY
    3. Sharf R
    4. Halachmi N
    5. Sun YH
    6. Salzberg A

    (1998)

    Dorsotonals/homothorax, the drosophila homologue of meis1, interacts with extradenticle in patterning of the embryonic PNS

    Development  125:1037–1048.

    • Google Scholar
61. 1. Kuruvilla R
    2. Ye H
    3. Ginty DD

    (2000)

    Spatially and functionally distinct roles of the PI3-k effector pathway during NGF signaling in sympathetic neurons

    Neuron 27:499–512.

    • Google Scholar
62. 1. Kuruvilla R
    2. Zweifel LS
    3. Glebova NO
    4. Lonze BE
    5. Valdez G
    6. Ye H
    7. Ginty DD

    (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling

    Cell 118:243–255.

    https://doi.org/10.1016/j.cell.2004.06.021

    • Google Scholar
63. 1. Kuwahara T
    2. Koyama A
    3. Koyama S
    4. Yoshina S
    5. Ren C-H
    6. Kato T
    7. Mitani S
    8. Iwatsubo T

    (2008) A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in -synuclein transgenic c. elegans

    Human Molecular Genetics 17:2997–3009.

    https://doi.org/10.1093/hmg/ddn198

    • Google Scholar
64. 1. Lei L
    2. Laub F
    3. Lush M
    4. Romero M
    5. Zhou J
    6. Luikart B
    7. Klesse L
    8. Ramirez F
    9. Parada LF

    (2005) The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons

    Genes & Development 19:1354–1364.

    https://doi.org/10.1101/gad.1227705

    • Google Scholar
65. 1. Leitner ML
    2. Molliver DC
    3. Osborne PA
    4. Vejsada R
    5. Golden JP
    6. Lampe PA
    7. Kato AC
    8. Milbrandt J
    9. Johnson EM

    (1999)

    Analysis of the retrograde transport of glial cell line-derived neurotrophic factor (gDNF), neurturin, and persephin suggests that in vivo signaling for the GDNF family is GFRalpha coreceptor-specific

    The Journal of Neuroscience  19:9322–9331.

    • Google Scholar
66. 1. Link MS
    2. Homoud MK
    3. Wang PJ
    4. Estes NA

    (2002)

    Cardiac arrhythmias in the athlete: the evolving role of electrophysiology

    Current Sports Medicine Reports 1:75–85.

    • Google Scholar
67. 1. Liu J-J
    2. Ding J
    3. Wu C
    4. Bhagavatula P
    5. Cui B
    6. Chu S
    7. Mobley WC
    8. Yang Y

    (2007) Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport

    Proceedings of the National Academy of Sciences of the United States of America 104:2223–2228.

    https://doi.org/10.1073/pnas.0602222104

    • Google Scholar
68. 1. Longobardi E
    2. Blasi F

    (2003) Overexpression of PREP-1 in F9 teratocarcinoma cells leads to a functionally relevant increase of PBX-2 by preventing its degradation

    The Journal of Biological Chemistry 278:39235–39241.

    https://doi.org/10.1074/jbc.M304704200

    • Google Scholar
69. 1. Lonze BE
    2. Riccio A
    3. Cohen S
    4. Ginty DD

    (2002)

    Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB

    Neuron 34:371–385.

    • Google Scholar
70. 1. MacInnis BL
    2. Senger DL
    3. Campenot RB

    (2003)

    Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons

    Neuropharmacology 45:995–1010.

    • Google Scholar
71. 1. Maden M

    (2007) Retinoic acid in the development, regeneration and maintenance of the nervous system

    Nature Reviews. Neuroscience 8:755–765.

    https://doi.org/10.1038/nrn2212

    • Google Scholar
72. 1. Mahmoud AI
    2. Kocabas F
    3. Muralidhar SA
    4. Kimura W
    5. Koura AS
    6. Thet S
    7. Porrello ER
    8. Sadek HA

    (2013) Meis1 regulates postnatal cardiomyocyte cell cycle arrest

    Nature 497:249–253.

    https://doi.org/10.1038/nature12054

    • Google Scholar
73. 1. Maina F
    2. Hilton MC
    3. Andres R
    4. Wyatt S
    5. Klein R
    6. Davies AM

    (1998)

    Multiple roles for hepatocyte growth factor in sympathetic neuron development

    Neuron 20:835–846.

    • Google Scholar
74. 1. Makita T
    2. Sucov HM
    3. Gariepy CE
    4. Yanagisawa M
    5. Ginty DD

    (2008) Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons

    Nature 452:759–763.

    https://doi.org/10.1038/nature06859

    • Google Scholar
75. 1. Malliani A
    2. Lombardi F
    3. Pagani M

    (1994)

    Power spectrum analysis of heart rate variability: a tool to explore neural regulatory mechanisms

    British Heart Journal 71:1–2.

    • Google Scholar
76. 1. Malliani A

    (1999)

    The pattern of sympathovagal balance explored in the frequency domain

    News in Physiological Sciences  14:111–117.

    • Google Scholar
77. 1. Manousiouthakis E
    2. Mendez M
    3. Garner MC
    4. Exertier P
    5. Makita T

    (2014) Venous endothelin guides sympathetic innervation of the developing mouse heart

    Nature Communications 5:3918.

    https://doi.org/10.1038/ncomms4918

    • Google Scholar
78. 1. Mansier P
    2. Clairambault J
    3. Charlotte N
    4. Médigue C
    5. Vermeiren C
    6. LePape G
    7. Carré F
    8. Gounaropoulou A
    9. Swynghedauw B

    (1996)

    Linear and non-linear analyses of heart rate variability: a minireview

    Cardiovascular Research 31:371–379.

    • Google Scholar
79. 1. Marmigère F
    2. Montelius A
    3. Wegner M
    4. Groner Y
    5. Reichardt LF
    6. Ernfors P

    (2006) The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons

    Nature Neuroscience 9:180–187.

    https://doi.org/10.1038/nn1631

    • Google Scholar
80. 1. Meester-Smoor MA
    2. Janssen MJ
    3. Grosveld GC
    4. de Klein A
    5. van IJcken WF
    6. Douben H
    7. Zwarthoff EC

    (2008) MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression

    Carcinogenesis 29:2025–2034.

    https://doi.org/10.1093/carcin/bgn168

    • Google Scholar
81. 1. Mercader N
    2. Leonardo E
    3. Piedra ME
    4. Martínez-A C
    5. Ros MA
    6. Torres M

    (2000)

    Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of meis genes

    Development  127:3961–3970.

    • Google Scholar
82. 1. Meyer L
    2. Stubbs B
    3. Fahrenbruch C
    4. Maeda C
    5. Harmon K
    6. Eisenberg M
    7. Drezner J

    (2012) Incidence, causes, and survival trends from cardiovascular-related sudden cardiac arrest in children and young adults 0 to 35 years of age: a 30-year review

    Circulation 126:1363–1372.

    https://doi.org/10.1161/CIRCULATIONAHA.111.076810

    • Google Scholar
83. 1. Mitchell GF
    2. Jeron A
    3. Koren G

    (1998)

    Measurement of heart rate and q-t interval in the conscious mouse

    The American Journal of Physiology 274:H747–H751.

    • Google Scholar
84. 1. Miwa K
    2. Lee JK
    3. Takagishi Y
    4. Opthof T
    5. Fu X
    6. Kodama I

    (2010)

    Glial cell line-derived neurotrophic factor (gDNF) enhances sympathetic neurite growth in rat hearts at early developmental stages

    Biomedical Research  31:353–361.

    • Google Scholar
85. 1. Moens CB
    2. Selleri L

    (2006) Hox cofactors in vertebrate development

    Developmental Biology 291:193–206.

    https://doi.org/10.1016/j.ydbio.2005.10.032

    • Google Scholar
86. 1. Moore MW
    2. Klein RD
    3. Fariñas I
    4. Sauer H
    5. Armanini M
    6. Phillips H
    7. Reichardt LF
    8. Ryan AM
    9. Carver-Moore K
    10. Rosenthal A

    (1996) Renal and neuronal abnormalities in mice lacking GDNF

    Nature 382:76–79.

    https://doi.org/10.1038/382076a0

    • Google Scholar
87. 1. Nakano Y
    2. Chayama K
    3. Ochi H
    4. Toshishige M
    5. Hayashida Y
    6. Miki D
    7. Hayes CN
    8. Suzuki H
    9. Tokuyama T
    10. Oda N
    11. Suenari K
    12. Uchimura-Makita Y
    13. Kajihara K
    14. Sairaku A
    15. Motoda C
    16. Fujiwara M
    17. Watanabe Y
    18. Yoshida Y
    19. Ohkubo K
    20. Watanabe I
    21. Nogami A
    22. Hasegawa K
    23. Watanabe H
    24. Endo N
    25. Aiba T
    26. Shimizu W
    27. Ohno S
    28. Horie M
    29. Arihiro K
    30. Tashiro S
    31. Makita N
    32. Kihara Y

    (2013) A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation

    PLoS Genetics 9:e1003364.

    https://doi.org/10.1371/journal.pgen.1003364

    • Google Scholar
88. 1. Nemani VM
    2. Lu W
    3. Berge V
    4. Nakamura K
    5. Onoa B
    6. Lee MK
    7. Chaudhry FA
    8. Nicoll RA
    9. Edwards RH

    (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis

    Neuron 65:66–79.

    https://doi.org/10.1016/j.neuron.2009.12.023

    • Google Scholar
89. 1. Nindl W
    2. Kavakebi P
    3. Claus P
    4. Grothe C
    5. Pfaller K
    6. Klimaschewski L

    (2004) Expression of basic fibroblast growth factor isoforms in postmitotic sympathetic neurons: synthesis, intracellular localization and involvement in karyokinesis

    Neuroscience 124:561–572.

    https://doi.org/10.1016/j.neuroscience.2003.11.032

    • Google Scholar
90. 1. Nishino J
    2. Mochida K
    3. Ohfuji Y
    4. Shimazaki T
    5. Meno C
    6. Ohishi S
    7. Matsuda Y
    8. Fujii H
    9. Saijoh Y
    10. Hamada H

    (1999) GFRα3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion

    Neuron 23:725–736.

    https://doi.org/10.1016/S0896-6273(01)80031-3

    • Google Scholar
91. 1. Parlato R
    2. Otto C
    3. Begus Y
    4. Stotz S
    5. Schütz G

    (2007) Specific ablation of the transcription factor CREB in sympathetic neurons surprisingly protects against developmentally regulated apoptosis

    Development  134:1663–1670.

    https://doi.org/10.1242/dev.02838

    • Google Scholar
92. 1. Penkov D
    2. Mateos San Martín D
    3. Fernandez-Díaz LC
    4. Rosselló CA
    5. Torroja C
    6. Sánchez-Cabo F
    7. Warnatz HJ
    8. Sultan M
    9. Yaspo ML
    10. Gabrieli A
    11. Tkachuk V
    12. Brendolan A
    13. Blasi F
    14. Torres M

    (2013) Analysis of the DNA-binding profile and function of TALE homeoproteins reveals their specialization and specific interactions with hox genes/proteins

    Cell Reports 3:1321–1333.

    https://doi.org/10.1016/j.celrep.2013.03.029

    • Google Scholar
93. 1. Pfeufer A
    2. van Noord C
    3. Marciante KD
    4. Arking DE
    5. Larson MG
    6. Smith AV
    7. Tarasov KV
    8. Müller M
    9. Sotoodehnia N
    10. Sinner MF
    11. Verwoert GC
    12. Li M
    13. Kao WH
    14. Köttgen A
    15. Coresh J
    16. Bis JC
    17. Psaty BM
    18. Rice K
    19. Rotter JI
    20. Rivadeneira F
    21. Hofman A
    22. Kors JA
    23. Stricker BH
    24. Uitterlinden AG
    25. van Duijn CM
    26. Beckmann BM
    27. Sauter W
    28. Gieger C
    29. Lubitz SA
    30. Newton-Cheh C
    31. Wang TJ
    32. Magnani JW
    33. Schnabel RB
    34. Chung MK
    35. Barnard J
    36. Smith JD
    37. Van Wagoner DR
    38. Vasan RS
    39. Aspelund T
    40. Eiriksdottir G
    41. Harris TB
    42. Launer LJ
    43. Najjar SS
    44. Lakatta E
    45. Schlessinger D
    46. Uda M
    47. Abecasis GR
    48. Müller-Myhsok B
    49. Ehret GB
    50. Boerwinkle E
    51. Chakravarti A
    52. Soliman EZ
    53. Lunetta KL
    54. Perz S
    55. Wichmann HE
    56. Meitinger T
    57. Levy D
    58. Gudnason V
    59. Ellinor PT
    60. Sanna S
    61. Kääb S
    62. Witteman JC
    63. Alonso A
    64. Benjamin EJ
    65. Heckbert SR

    (2010) Genome-wide association study of PR interval

    Nature Genetics 42:153–159.

    https://doi.org/10.1038/ng.517

    • Google Scholar
94. 1. Philippidou P
    2. Valdez G
    3. Akmentin W
    4. Bowers WJ
    5. Federoff HJ
    6. Halegoua S

    (2011) Trk retrograde signaling requires persistent, pincher-directed endosomes

    Proceedings of the National Academy of Sciences of the United States of America 108:852–857.

    https://doi.org/10.1073/pnas.1015981108

    • Google Scholar
95. 1. Pietri T
    2. Eder O
    3. Blanche M
    4. Thiery JP
    5. Dufour S

    (2003)

    The human tissue plasminogen activator-cre mouse: a new tool for targeting specifically neural crest cells and their derivatives in vivo

    Developmental Biology 259:176–187.

    • Google Scholar
96. 1. Plum LA
    2. Clagett-Dame M

    (1996) All-trans retinoic acid stimulates and maintains neurite outgrowth in nerve growth factor-supported developing chick embryonic sympathetic neurons

    Developmental Dynamics  205:52–63.

    https://doi.org/10.1002/(SICI)1097-0177(199601)205:1<52::AID-AJA5>3.0.CO;2-4

    • Google Scholar
97. 1. Plum LA
    2. Parada LF
    3. Tsoulfas P
    4. Clagett-Dame M

    (2001)

    Retinoic acid combined with neurotrophin-3 enhances the survival and neurite outgrowth of embryonic sympathetic neurons

    Experimental Biology and Medicine 226:766–775.

    • Google Scholar
98. 1. Qin P
    2. Cimildoro R
    3. Kochhar DM
    4. Soprano KJ
    5. Soprano DR

    (2002) PBX, MEIS, and IGF-i are potential mediators of retinoic acid-induced proximodistal limb reduction defects

    Teratology 66:224–234.

    https://doi.org/10.1002/tera.10082

    • Google Scholar
99. 1. Rataj-Baniowska M
    2. Niewiadomska-Cimicka A
    3. Paschaki M
    4. Szyszka-Niagolov M
    5. Carramolino L
    6. Torres M
    7. Dollé P
    8. Krężel W

    (2015) Retinoic acid receptor β controls development of striatonigral projection neurons through FGF-dependent and Meis1-dependent mechanisms

    The Journal of Neuroscience  35:14467–14475.

    https://doi.org/10.1523/JNEUROSCI.1278-15.2015

    • Google Scholar
100. 1. Reis RAM
     2. Cabral da Silva MC
     3. Loureiro dos Santos NE
     4. Bampton E
     5. Taylor JSH
     6. de Mello FG
     7. Linden R

     (2002) Sympathetic neuronal survival induced by retinal trophic factors

     Journal of Neurobiology 50:13–23.

     https://doi.org/10.1002/neu.10008

     • Google Scholar
101. 1. Repa JJ
     2. Plum LA
     3. Tadikonda PK
     4. Clagett-Dame M

     (1996)

     All-trans 3,4-didehydroretinoic acid equals all-trans retinoic acid in support of chick neuronal development

     FASEB Journal  10:1078–1084.

     • Google Scholar
102. 1. Riccio A
     2. Ahn S
     3. Davenport CM
     4. Blendy JA
     5. Ginty DD

     (1999)

     Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons

     Science  286:2358–2361.

     • Google Scholar
103. 1. Riccio A
     2. Pierchala BA
     3. Ciarallo CL
     4. Ginty DD

     (1997)

     An NGF-TrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons

     Science  277:1097–1100.

     • Google Scholar
104. 1. Rizo J
     2. Rosenmund C

     (2008) Synaptic vesicle fusion

     Nature Structural & Molecular Biology 15:665–674.

     https://doi.org/10.1038/nsmb.1450

     • Google Scholar
105. 1. Roberts RL
     2. Barbieri MA
     3. Pryse KM
     4. Chua M
     5. Morisaki JH
     6. Stahl PD

     (1999)

     Endosome fusion in living cells overexpressing GFP-rab5

     Journal of Cell Science 112:3667–3675.

     • Google Scholar
106. 1. Rodriguez-Tébar A
     2. Rohrer H

     (1991)

     Retinoic acid induces NGF-dependent survival response and high-affinity NGF receptors in immature chick sympathetic neurons

     Development  112:813–820.

     • Google Scholar
107. 1. Rohrer H

     (2011) Transcriptional control of differentiation and neurogenesis in autonomic ganglia

     The European Journal of Neuroscience 34:1563–1573.

     https://doi.org/10.1111/j.1460-9568.2011.07860.x

     • Google Scholar
108. 1. Rydel RE
     2. Greene LA

     (1987)

     Acidic and basic fibroblast growth factors promote stable neurite outgrowth and neuronal differentiation in cultures of PC12 cells

     The Journal of Neuroscience  7:3639–3653.

     • Google Scholar
109. 1. Schneider CA
     2. Rasband WS
     3. Eliceiri KW

     (2012) NIH image to ImageJ: 25 years of image analysis

     Nature Methods 9:671–675.

     https://doi.org/10.1038/nmeth.2089

     • Google Scholar
110. 1. Sgado P
     2. Alberi L
     3. Gherbassi D
     4. Galasso SL
     5. Ramakers GMJ
     6. Alavian KN
     7. Smidt MP
     8. Dyck RH
     9. Simon HH

     (2006) Slow progressive degeneration of nigral dopaminergic neurons in postnatal engrailed mutant mice

     Proceedings of the National Academy of Sciences of the United States of America 103:15242–15247.

     https://doi.org/10.1073/pnas.0602116103

     • Google Scholar
111. 1. Shanmugam K
     2. Green NC
     3. Rambaldi I
     4. Saragovi HU
     5. Featherstone MS

     (1999) PBX and MEIS as non-DNA-binding partners in trimeric complexes with HOX proteins

     Molecular and Cellular Biology 19:7577–7588.

     https://doi.org/10.1128/MCB.19.11.7577

     • Google Scholar
112. 1. Shim S
     2. Kim Y
     3. Shin J
     4. Kim J
     5. Park S

     (2007) Regulation of EphA8 gene expression by TALE homeobox transcription factors during development of the mesencephalon

     Molecular and Cellular Biology 27:1614–1630.

     https://doi.org/10.1128/MCB.01429-06

     • Google Scholar
113. 1. Simon HH
     2. Saueressig H
     3. Wurst W
     4. Goulding MD
     5. O'Leary DD

     (2001)

     Fate of midbrain dopaminergic neurons controlled by the engrailed genes

     Journal of Neuroscience 21:3126–3134.

     • Google Scholar
114. 1. Simon HH
     2. Thuret S
     3. Alberi L

     (2004) Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors

     Cell and Tissue Research 318:53–61.

     https://doi.org/10.1007/s00441-004-0973-8

     • Google Scholar
115. 1. Smeyne RJ
     2. Klein R
     3. Schnapp A
     4. Long LK
     5. Bryant S
     6. Lewin A
     7. Lira SA
     8. Barbacid M

     (1994) Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene

     Nature 368:246–249.

     https://doi.org/10.1038/368246a0

     • Google Scholar
116. 1. Smith JG
     2. Magnani JW
     3. Palmer C
     4. Meng YA
     5. Soliman EZ
     6. Musani SK
     7. Kerr KF
     8. Schnabel RB
     9. Lubitz SA
     10. Sotoodehnia N
     11. Redline S
     12. Pfeufer A
     13. Müller M
     14. Evans DS
     15. Nalls MA
     16. Liu Y
     17. Newman AB
     18. Zonderman AB
     19. Evans MK
     20. Deo R
     21. Ellinor PT
     22. Paltoo DN
     23. Newton-Cheh C
     24. Benjamin EJ
     25. Mehra R
     26. Alonso A
     27. Heckbert SR
     28. Fox ER
     29. Candidate-gene Association Resource (CARe) Consortium

     (2011) Genome-wide association studies of the PR interval in african americans

     PLoS Genetics 7:e1001304.

     https://doi.org/10.1371/journal.pgen.1001304

     • Google Scholar
117. 1. Stankunas K
     2. Shang C
     3. Twu KY
     4. Kao SC
     5. Jenkins NA
     6. Copeland NG
     7. Sanyal M
     8. Selleri L
     9. Cleary ML
     10. Chang CP

     (2008) Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease

     Circulation Research 103:702–709.

     https://doi.org/10.1161/CIRCRESAHA.108.175489

     • Google Scholar
118. 1. Stemple DL
     2. Mahanthappa NK
     3. Anderson DJ

     (1988)

     Basic FGF induces neuronal differentiation, cell division, and NGF dependence in chromaffin cells: a sequence of events in sympathetic development

     Neuron 1:517–525.

     • Google Scholar
119. 1. Stramba-Badiale M
     2. Lazzarotti M
     3. Schwartz PJ

     (1992)

     Development of cardiac innervation, ventricular fibrillation, and sudden infant death syndrome

     The American Journal of Physiology 263:H1514–H1522.

     • Google Scholar
120. 1. Suo D
     2. Park J
     3. Harrington AW
     4. Zweifel LS
     5. Mihalas S
     6. Deppmann CD

     (2014) Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival

     Nature Neuroscience 17:36–45.

     https://doi.org/10.1038/nn.3593

     • Google Scholar
121. 1. Takei K
     2. Haucke V

     (2001)

     Clathrin-mediated endocytosis: membrane factors pull the trigger

     Trends in Cell Biology 11:385–391.

     • Google Scholar
122. 1. Tanaka A
     2. Kamiakito T
     3. Hakamata Y
     4. Fujii A
     5. Kuriki K
     6. Fukayama M

     (2001) Extensive neuronal localization and neurotrophic function of fibroblast growth factor 8 in the nervous system

     Brain Research 912:105–115.

     https://doi.org/10.1016/S0006-8993(01)02726-3

     • Google Scholar
123. 1. Tankersley CG
     2. Campen M
     3. Bierman A
     4. Flanders SE
     5. Broman KW
     6. Rabold R

     (2004) Particle effects on heart-rate regulation in senescent mice

     Inhalation Toxicology 16:381–390.

     https://doi.org/10.1080/08958370490439551

     • Google Scholar
124. 1. Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology

     (1996)

     Heart rate variability: standards of measurement, physiological interpretation and clinical use. task force of the european society of cardiology and the north american society of pacing and electrophysiology

     Circulation 93:1043–1065.

     • Google Scholar
125. 1. Thang SH
     2. Kobayashi M
     3. Matsuoka I

     (2000)

     Regulation of glial cell line-derived neurotrophic factor responsiveness in developing rat sympathetic neurons by retinoic acid and bone morphogenetic protein-2

     Journal of Neuroscience 20:2917–2925.

     • Google Scholar
126. 1. Thireau J
     2. Zhang BL
     3. Poisson D
     4. Babuty D

     (2008) Heart rate variability in mice: a theoretical and practical guide

     Experimental Physiology 93:83–94.

     https://doi.org/10.1113/expphysiol.2007.040733

     • Google Scholar
127. 1. Toresson H
     2. Parmar M
     3. Campbell K

     (2000) Expression of meis and pbx genes and their protein products in the developing telencephalon: implications for regional differentiation

     Mechanisms of Development 94:183–187.

     https://doi.org/10.1016/S0925-4773(00)00324-5

     • Google Scholar
128. 1. Trupp M
     2. Rydén M
     3. Jörnvall H
     4. Funakoshi H
     5. Timmusk T
     6. Arenas E
     7. Ibáñez CF

     (1995)

     Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons

     The Journal of Cell Biology 130:137–148.

     • Google Scholar
129. 1. Tsarovina K
     2. Pattyn A
     3. Stubbusch J
     4. Müller F
     5. van der Wees J
     6. Schneider C
     7. Brunet JF
     8. Rohrer H

     (2004) Essential role of gata transcription factors in sympathetic neuron development

     Development 131:4775–4786.

     https://doi.org/10.1242/dev.01370

     • Google Scholar
130. 1. Tsui CC
     2. Pierchala BA

     (2010) The differential axonal degradation of ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor

     The Journal of Neuroscience  30:5149–5158.

     https://doi.org/10.1523/JNEUROSCI.5246-09.2010

     • Google Scholar
131. 1. Uechi M
     2. Asai K
     3. Osaka M
     4. Smith A
     5. Sato N
     6. Wagner TE
     7. Ishikawa Y
     8. Hayakawa H
     9. Vatner DE
     10. Shannon RP
     11. Homcy CJ
     12. Vatner SF

     (1998)

     Depressed heart rate variability and arterial baroreflex in conscious transgenic mice with overexpression of cardiac gsalpha

     Circulation Research 82:416–423.

     • Google Scholar
132. 1. Unnisa Z
     2. Clark JP
     3. Roychoudhury J
     4. Thomas E
     5. Tessarollo L
     6. Copeland NG
     7. Jenkins NA
     8. Grimes HL
     9. Kumar AR

     (2012) Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress

     Blood 120:4973–4981.

     https://doi.org/10.1182/blood-2012-06-435800

     • Google Scholar
133. 1. Valdez G
     2. Akmentin W
     3. Philippidou P
     4. Kuruvilla R
     5. Ginty DD
     6. Halegoua S

     (2005) Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors

     The Journal of Neuroscience  25:5236–5247.

     https://doi.org/10.1523/JNEUROSCI.5104-04.2005

     • Google Scholar
134. 1. Valdez G
     2. Philippidou P
     3. Rosenbaum J
     4. Akmentin W
     5. Shao Y
     6. Halegoua S

     (2007) Trk-signaling endosomes are generated by rac-dependent macroendocytosis

     Proceedings of the National Academy of Sciences of the United States of America 104:12270–12275.

     https://doi.org/10.1073/pnas.0702819104

     • Google Scholar
135. 1. Vargas KJ
     2. Makani S
     3. Davis T
     4. Westphal CH
     5. Castillo PE
     6. Chandra SS

     (2014) Synucleins regulate the kinetics of synaptic vesicle endocytosis

     The Journal of Neuroscience  34:9364–9376.

     https://doi.org/10.1523/JNEUROSCI.4787-13.2014

     • Google Scholar
136. 1. Varsano T
     2. Dong MQ
     3. Niesman I
     4. Gacula H
     5. Lou X
     6. Ma T
     7. Testa JR
     8. Yates JR
     9. Farquhar MG

     (2006) GIPC is recruited by APPL to peripheral TrkA endosomes and regulates TrkA trafficking and signaling

     Molecular and Cellular Biology 26:8942–8952.

     https://doi.org/10.1128/MCB.00305-06

     • Google Scholar
137. 1. von Holst A
     2. Rodriguez-Tébar A
     3. Michaille JJ
     4. Dhouailly D
     5. Bäckström A
     6. Ebendal T
     7. Rohrer H

     (1995)

     Retinoic acid-mediated increase in TrkA expression is sufficient to elicit NGF-dependent survival of sympathetic neurons

     Molecular and Cellular Neurosciences 6:185–198.

     • Google Scholar
138. 1. Walker MJ
     2. Curtis MJ
     3. Hearse DJ
     4. Campbell RW
     5. Janse MJ
     6. Yellon DM
     7. Cobbe SM
     8. Coker SJ
     9. Harness JB
     10. Harron DW

     (1988)

     The lambeth conventions: guidelines for the study of arrhythmias in ischaemia infarction, and reperfusion

     Cardiovascular Research 22:447–455.

     • Google Scholar
139. 1. Wilson NK
     2. Foster SD
     3. Wang X
     4. Knezevic K
     5. Schütte J
     6. Kaimakis P
     7. Chilarska PM
     8. Kinston S
     9. Ouwehand WH
     10. Dzierzak E
     11. Pimanda JE
     12. de Bruijn MF
     13. Göttgens B

     (2010) Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators

     Cell Stem Cell 7:532–544.

     https://doi.org/10.1016/j.stem.2010.07.016

     • Google Scholar
140. 1. Wyatt S
     2. Andres R
     3. Rohrer H
     4. Davies AM

     (1999)

     Regulation of neurotrophin receptor expression by retinoic acid in mouse sympathetic neuroblasts

     The Journal of Neuroscience  19:1062–1071.

     • Google Scholar
141. 1. Ye H
     2. Kuruvilla R
     3. Zweifel LS
     4. Ginty DD

     (2003) Evidence in support of signaling endosome-based retrograde survival of sympathetic neurons

     Neuron 39:57–68.

     https://doi.org/10.1016/S0896-6273(03)00266-6

     • Google Scholar
142. 1. Yun AJ
     2. Lee PY

     (2004) Sudden death among infants and adults: companion disorders of maladaptive sympathetic bias

     Medical Hypotheses 62:857–860.

     https://doi.org/10.1016/j.mehy.2003.11.014

     • Google Scholar
143. 1. Zhang JZ
     2. Davletov BA
     3. Südhof TC
     4. Anderson RG

     (1994)

     Synaptotagmin i is a high affinity receptor for clathrin AP-2: implications for membrane recycling

     Cell 78:751–760.

     • Google Scholar

Author details

1. Fabrice Bouilloux

   Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France

   Contribution

   FB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Jérôme Thireau

   Competing interests

   The authors declare that no competing interests exist.

2. Jérôme Thireau

   Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France

   Contribution

   JT, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Contributed equally with

   Fabrice Bouilloux

   Competing interests

   The authors declare that no competing interests exist.

3. Stéphanie Ventéo

   Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France

   Contribution

   SV, Conception and design, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Charlotte Farah

   Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France

   Contribution

   CF, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Sarah Karam

   Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France

   Contribution

   SK, Conception and design, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Yves Dauvilliers

   Sleep Unit, Department of Neurology, Gui-de-Chauliac hospital, Montpellier, France

   Contribution

   YD, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

7. Jean Valmier

   Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France

   Contribution

   JV, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

8. Neal G Copeland

   Cancer Research Program, The Methodist Hospital Research Institute, Houston, United States

   Contribution

   NGC, Conception and design, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

9. Nancy A Jenkins

   Cancer Research Program, The Methodist Hospital Research Institute, Houston, United States

   Contribution

   NAJ, Conception and design, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

10. Sylvain Richard

    Physiologie et Médecine Expérimentale du cœur et des Muscles, INSERM U1046, CNRS UMR 9214, University of Montpellier, Montpellier, France

    Contribution

    SR, Conception and design, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    Competing interests

    The authors declare that no competing interests exist.

11. Frédéric Marmigère

    Institute for Neurosciences of Montpellier, Institut national de la santé et de la recherche médicale, Montpellier, France

    Contribution

    FM, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

    For correspondence

    frederic.marmigere@inserm.fr

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-0515-7483