The mammalian neocortex has a complicated structure, with multiple layers of different types of neurons linked together in microcircuits. Cortical neurons are generated by progenitor divisions at or near the ventricular zone (VZ), then migrate to defined positions in the developing cortical plate (CP) where they differentiate and connect among themselves and to other brain regions. In general, projection neurons arise from the local VZ, below the CP, while interneurons migrate tangentially from the ganglionic eminences (Parnavelas, 2000; Rash and Grove, 2006). The projection neurons are layered in birth order, such that neurons born early in development are below those born later (Takahashi et al., 1999). Correct neuron layering is important: major defects in projection neuron migration may underlie lissencephalies and heterotopias coupled with mental retardation while milder defects are associated with mental disabilities including dyslexia, schizophrenia, epilepsy, and autism spectrum disorders (Bielas et al., 2004; Francis et al., 2006; Romero et al., 2018). A great deal is known about the distinct neuron migration paths and the signals that regulate them but a significant number of patients with developmental disorders lack a diagnosis. It is thus crucial to identify further causes of disease and understand them mechanistically.

Migrating projection neurons have been visualized in fetal mouse brains in which individual neurons have been labeled in utero (Tabata and Nakajima, 2001; Nadarajah and Parnavelas, 2002; Noctor et al., 2004). Migration occurs in distinct phases. First, neurons move radially from the VZ into the lower intermediate zone (IZ). They then become multipolar and despite an apparent irregular movement, move towards the CP (Nadarajah et al., 2003; Tabata and Nakajima, 2003; Noctor et al., 2004; Jossin and Cooper, 2011). When multipolar neurons reach the upper IZ, they become bipolar and traverse the CP by glial-guided locomotion. The lower IZ therefore constitutes a multipolar migration zone (MMZ) and the upper IZ and CP a radial migration zone (RMZ). Movement out of the MMZ is regulated by many signals, which, if disrupted, can lead to altered layering (Cooper, 2014; Kon et al., 2017). One signal that regulates exit from the MMZ is Reelin, an extracellular matrix protein that activates the small GTPases Rap1A and RalA to upregulate surface levels of neural cadherin (NCad, CDH2) (Jossin, 2011; Jossin and Cooper, 2011). Inhibiting Reelin, Rap1 or NCad interferes with the orientation of multipolar neurons, increases sideways and downwards movements, and increases time spent in the MMZ. Defects in multipolar migration may contribute to the altered layering in Reelin mutant mice and humans (Lambert de Rouvroit and Goffinet, 1998; Hong et al., 2000).

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are important during the development of many tissues and for wound healing, tissue repair and metabolism after birth (Beenken and Mohammadi, 2009; Ornitz and Itoh, 2015). There is wide functional redundancy between family members, with specificity conferred by cell-type-specific expression of FGFs and FGFRs and alternative splicing of FGFRs. At the cellular level, FGFRs regulate cell proliferation, migration, differentiation, survival and cell shape. At the molecular level, FGF and heparan sulfate proteoglycan bind to FGFRs and induce FGFR dimerization and activation. Activated FGFRs autophosphorylate on multiple cytoplasmic tyrosine residues, followed by recruitment and phosphorylation of a variety of downstream signaling proteins (Ornitz and Itoh, 2015). Following activation, FGFRs are down-regulated by ubiquitination, endocytosis and lysosomal degradation (Katzmann et al., 2002; Haugsten et al., 2005). Defects in FGFR activation or down-regulation can lead to anomalous signaling and are associated with developmental defects, metabolic disorders and cancer (Wesche et al., 2011; Ornitz and Itoh, 2015).

In addition to FGFs and heparan sulfate, cell surface proteins including neural cadherin (NCad or CDH2), epidermal cadherin (ECad or CDH1), L1 cell adhesion molecule (L1CAM) and neural CAM (NCAM) can also bind to and activate FGFRs (Williams et al., 1994; Williams et al., 2001; Suyama et al., 2002; Brown et al., 2016). Both NCad and FGFRs are highly expressed during the epithelial-mesenchymal transition of cancer cells and their interaction may be important for metastasis. Indeed, tumor cells artificially over-expressing NCad require FGFR activity for metastasis. Nevertheless, the role of NCad-dependent FGFR activation in metastasis pathology remains unclear (Hulit et al., 2007; Qian et al., 2014).

In the developing cerebral cortex FGFR1-3 are expressed in the VZ and MMZ (Iwata and Hevner, 2009; Hébert, 2011) (Allen Institute for Brain Science. Allen Developing Mouse Brain Atlas. Available from: http://developingmouse.brain-map.org/) and FGFRs have been associated with neurodevelopmental diseases including schizophrenia (O'Donovan et al., 2009; Terwisscha van Scheltinga et al., 2013), epilepsy (Coci et al., 2017; Okazaki et al., 2017), autism spectrum disorders (Wentz et al., 2014; Coci et al., 2017) and lissencephaly (Tan and Mankad, 2018), suggesting possible roles in neuron migration. However, analysis of cortical neuron migration in FGFR mutant mice has been inconclusive for two reasons. First, functional redundancy may suppress the phenotypes of loss of function mutants (Beenken and Mohammadi, 2009; Hébert, 2011; Ornitz and Itoh, 2015). Second, FGFRs are needed for developmental steps that occur before migration, such as regional patterning of the cortex, neurogenesis and radial glia differentiation (Shin et al., 2004; Rash and Grove, 2006; Mason, 2007; Kang et al., 2009; Paek et al., 2009). Therefore, the roles of FGFRs in neocortical neuron migration are unclear.

In this paper we report that FGFR1-3 have overlapping functions during the multipolar migration in vivo. FGFRs are required downstream of Rap1 for multipolar cells to orient towards the CP, adopt bipolar morphology, and migrate out of the MMZ. We found that Rap1-dependent NCad upregulation stabilizes FGFRs by inhibiting K27- and K29-linked polyubiquitination and lysosomal degradation and that NCad-FGFR cis interaction (on the same cell) is involved. Consequently, FGFRs accumulate and are activated, resulting in prolonged activation of Erk1/2 when neurons are stimulated in vitro with Reelin. In vivo inhibition of K27-linked polyubiquitination or overexpression of FGFRs rescues the migration of neurons with inhibited Rap1. Inhibition of Erk1/2 activity in the developing cerebral cortex induces a similar phenotype as FGFR or Rap1 inhibition. These data reveal a novel function of FGFRs in cortical projection neuron migration and the control of its activity by ubiquitination and NCad interaction in vivo. To our knowledge, this is the first physiological role for FGFR-NCad interaction during tissue development. Furthermore, we identified FGFRs as mediating Reelin activation of Erk1/2 to control migration during the multipolar phase. These findings provide insights into FGFR mutation-related inherited brain diseases.

Although much is known about the role of FGFRs in apical neural stem cells during neurogenesis and regional patterning of the cortex, the functions and regulation of FGFRs in neuronal migration have not been elucidated. Our findings implicate FGFRs in a signaling pathway that regulates the orientation of projection neuron multipolar migration during the development of the cerebral cortex (see our working model Figure 9b). When FGFRs are inhibited, multipolar neurons accumulate in the multipolar migration zone. This includes a defect in the orientation of multipolar migration with fewer cells facing the CP, followed by a delay in the multipolar to radial morphology transition and a consequent accumulation of cells at the MMZ. Previous studies indicated that the orientation of multipolar migration and the subsequent bipolar morphology transition is triggered by Reelin, or the R3-6 fragment, diffusing from the outer part of the cortex (Jossin et al., 2004; Jossin et al., 2007; Uchida et al., 2009; Jossin and Cooper, 2011). Reelin activates Rap1, and this in turn upregulates NCad on the neuron surface (Jossin and Cooper, 2011). However, the mechanism by which NCad stimulates the multipolar migration was unknown. One possibility was that NCad on migrating neurons engages in homophilic binding interactions with NCad on surrounding cells (Kawauchi et al., 2010; Matsunaga et al., 2017). However, our new evidence leads us to propose a model in which NCad-NCad trans interactions are not required. Instead, NCad binds in cis to FGFRs on the same cell. This cell-autonomous binding inhibits FGFR K27/K29 polyubiquitination and lysosomal degradation, resulting in a large increase in FGFR abundance and prolonged activation of FGFR and Erk1/2 that is required for the multipolar migration. FGFR-dependent Erk1/2 stimulation may therefore be a key signal for orienting multipolar neurons towards the CP.

FGFRs have been implicated in other developmental cell movements, including migration of mesodermal and tracheal cells in Drosophila (Gisselbrecht et al., 1996; Lebreton and Casanova, 2016), neuroblasts in the mouse olfactory bulb (Zhou et al., 2015) and keratinocytes during repair of epidermal injury (Meyer et al., 2012). A possible role for FGFRs in cortical projection neuron migration has not been reported previously, perhaps because FGFRs are needed for early telencephalon patterning and neurogenesis, and because of functional redundancy (Kang et al., 2009; Paek et al., 2009). Cortical layering was defective in a mouse model expressing dominant-negative FGFR1 during neurogenesis but this could be secondary to the defective radial glia processes (Shin et al., 2004). By inhibiting FGFR signaling in postmitotic neurons, we avoided effects on neurogenesis or radial glia processes. Under these conditions, neurons were delayed in the multipolar migration zone, with randomized orientation, suggesting that FGFRs provide directional information. Conventionally, FGFRs are activated by FGFs and heparan sulfate proteoglycans (Ornitz and Itoh, 2015), so directional information could be provided by an FGF gradient, serving as a chemorepellent or attractant, as in the Drosophila trachea (Lebreton and Casanova, 2016). However, a large number of FGFs are expressed in the developing cortex (Ford-Perriss et al., 2001), making it challenging to identify which, if any, may be involved. It is also possible that NCad activates FGFRs in the absence of FGFs. Reelin could stimulate FGFR-dependent Erk1/2 activity in cultured neurons in the absence of added FGF, suggesting that external FGF may not be needed in vivo. The co-clustering of FGFRs with NCad may be sufficient to activate the receptor independently of FGF, with FGFRs acting as ‘catalytic subunits’ downstream of NCad. A similar mechanism has been suggested for activation by the co-receptor Klotho (Lee et al., 2018).

Our cell culture experiments suggest that NCad stabilizes cell-surface FGFR by inhibiting K27/K29-linked polyubiquitination and lysosomal degradation. Importantly, inhibiting K27-linked polyubiquitination by expression of a mutant ubiquitin rescued the migration of Rap1-inhibited neurons, suggesting that this mechanism also occurs in vivo. The involvement of K27 and K29 is unusual. Polyubiquitin chains assemble through any of seven lysine residues on the ubiquitin molecule, resulting in diverse outcomes for the target protein (Fushman and Wilkinson, 2011). While K11 and K48 polyubiquitination is linked to proteasomal degradation and K63 polyubiquitination to lysosomal degradation, the roles of K6-, K27-, K29-, and of K33-linked ubiquitin chains are less clear (Sadowski et al., 2012). K27 and K29 ubiquitin linkages have been implicated in protein interactions and protein degradation (Chastagner et al., 2006; Ikeda and Kerppola, 2008; Zotti et al., 2011; Fei et al., 2013; Zhou et al., 2013; Birsa et al., 2014; Liu et al., 2014). We found here that both K27 and K29 ubiquitin linkages are necessary for FGFR lysosomal degradation. This may involve mixed linear or mixed branched ubiquitin chains or single K27 and K29 chains attached to different lysine residues on the cytoplasmic tail of FGFRs (Yau and Rape, 2016). The E3 ligase and mechanism of lysosomal targeting remains unclear.

ECad also binds FGFRs but, unlike NCad, does not inhibit FGFR ubiquitination, protect FGFRs from degradation, or regulate multipolar migration in vivo. Using mutated receptors and chimeric proteins, we found that FGFRs bind both ECad and NCad and that binding is necessary but not sufficient to stabilize FGFRs and stimulate multipolar migration. Binding requires the fourth NCad EC domain, but FGFR stabilization and neuronal migration rescue also require the first two NCad domains. Their function is unclear. They may bind to a third partner in the complex that helps NCad inhibit FGFR degradation.

Our results indicated that Reelin does not activate ERK signaling directly but does so by stabilizing FGFR. ERK phosphorylation was delayed, presumably due to the time necessary to accumulate sufficient FGFR. A prolonged Erk1/2 activation might be required to induce a signal as is the case for EGF-induced neuronal differentiation of PC12 cells (Traverse et al., 1994). For instance, Erk1/2 signaling has been linked to transcription of matrix metalloproteinases genes (Westermarck and Kahari, 1999) and some metalloproteinases are essential for the organization of the cerebral cortex (Jorissen et al., 2010). Interestingly, Erk1 and Erk2 double mutant mice exhibit a defect in cortical lamination (Imamura et al., 2010). A cell-autonomous function of Erk1/2 signaling could not be determined because of a failure in maintenance of the radial glia scaffolding. However, our results indicate that Erk1/2 activity is required in migrating neurons during the multipolar phase.

While we were writing this manuscript, FGFR2 was reported to regulate neuronal migration and spine density (Szczurkowska et al., 2018). Defective mice showed impaired core behaviors related to autism spectrum disorders. Interestingly, the Reelin pathway also regulates spine density and has been linked to autism (Niu et al., 2008; Lammert and Howell, 2016). Reelin was also reported to regulate the migration of dopaminergic neurons into the substantia nigra, with induction of bipolar morphology (Vaswani et al., 2019). Additional research will be needed to elucidate the mechanism of FGFRs in Reelin-induced migration and spine density and the link with autism spectrum disorders.

All data generated or analyzed during this study are included in the manuscript and supporting files.

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Author details

1. Elif Kon

   Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Performed most of the biochemistry and histology experiments, Assisted with preparing the manuscript

   Competing interests

   No competing interests declared

2. Elisa Calvo-Jiménez

   Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Assisted with the biochemistry and histology experiments, Performed the primary cortical neuron nucleofection experiments, Assisted with preparing the manuscript

   Competing interests

   No competing interests declared

3. Alexia Cossard

   Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

   Contribution

   Investigation, Visualization, Assisted with the biochemistry and histology experiments, Assisted with preparing the manuscript

   Competing interests

   No competing interests declared

4. Youn Na

   Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   Investigation, Assisted with the biochemistry and histology experiments, Assisted with preparing the manuscript

   Competing interests

   No competing interests declared

5. Jonathan A Cooper

   Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   Writing—review and editing, Reviewed and edited the final version of the manuscript, Assisted with preparing the manuscript

   Competing interests

   Senior editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-8626-7827

6. Yves Jossin

   Laboratory of Mammalian Development & Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing, Conceived and supervised the project, Designed all experiments, Wrote the original draft of the manuscript, Reviewed and edited the final version of the manuscript, Performed the in vivo experiments

   For correspondence

   yves.jossin@uclouvain.be

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8466-7432

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