Communication between cells depends on their ability to respond as integrated units to spatial and temporal signalling patterns. The complex morphology of neurons provides an unrivalled model to study how sorting and trafficking of signalling complexes coordinate local signalling at axon terminals and the propagation of messages to the cell body. A clear example is provided by neurotrophic factors secreted by target tissues and sensed by axon terminals, where, among other functions, they regulate local cytoskeletal dynamics to promote or cease axon elongation, induce branching, as well as synaptic maturation and plasticity (Andres-Alonso et al., 2019; Szobota et al., 2019; Woo et al., 2019). At the same time, a population of activated receptors are internalised and targeted to the retrograde axonal transport pathway within signalling endosomes (Barford et al., 2017; Villarroel-Campos et al., 2018), which propagate neurotrophic signalling towards the cell body, regulating gene expression, dendritic branching, and the balance between survival and apoptosis (Du and Poo, 2004; Pazyra-Murphy et al., 2009; Watson et al., 1999; Zhou et al., 2012). How local and central responses are coordinated across the massive distance from axon terminals to the soma is a crucial and still unanswered question for neuronal cell biology.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is widely expressed in the central nervous system, together with its receptor tropomyosin-related kinase B (TrkB). By activating diverse signalling cascades, comprising the phosphoinositide 3‐kinase (PI3K)‐Akt pathway, mitogen‐activated protein kinases (MAPKs), and phospholipase C‐gamma (PLCγ), BDNF and TrkB play a critical role in the formation, maintenance, and plasticity of neuronal circuits (Huang and Reichardt, 2003; Minichiello, 2009). Binding of BDNF at synaptic sites leads to endocytosis of TrkB and entry of the activated ligand–receptor complexes in early endosomes (Deinhardt et al., 2006). Whilst part of internalised TrkB recycle back to the plasma membrane, a pool of receptors is sorted to signalling endosomes and engage with the cytoplasmic dynein motor complex, which mediates the transport of these organelles to the soma (Andres-Alonso et al., 2019; Ha et al., 2008; Zhou et al., 2012). Independent lines of evidence indicate that this compartment is generated from early endosomes that then mature into a more specialised organelle escaping acidification and lysosomal degradation (Villarroel-Campos et al., 2018). Sorting of TrkB receptors from early to signalling endosomes constitutes the critical regulatory node controlling the intensity of the retrogradely propagated signal; however, to date, no clear mechanism controlling this sorting process has been elucidated.

The Rab family of monomeric GTPases plays a central role regulating post-endocytic trafficking of TrkB. Whilst early endosome formation is regulated by Rab5, maturation and processive transport of signalling endosomes in different neuronal models are controlled by Rab7 (Bucci et al., 2014; Burk et al., 2017; Deinhardt et al., 2006; Kucharava et al., 2020). However, it is currently unclear whether or not Rab7 is the only member of the Rab family necessary for the latter process. Because axonal retrograde signalling endosomes appear to be a diverse group of organelles (Villarroel-Campos et al., 2018), we hypothesised that other members of the Rab family also contribute to the segregation of TrkB and its sorting to retrograde axonal carriers.

In this work, we specifically focused on Rab10 since it has been shown that Rab10-positive organelles are transported both anterogradely and retrogradely along axons in hippocampal neurons (Deng et al., 2014). Previous work from our laboratory using an affinity purification approach to isolate neurotrophin signalling endosomes from mouse embryonic stem cell‐derived motor neurons found that Rab10 was significantly enriched in this axonal compartment, which is also characterised by the presence of Rab5 and Rab7 (Debaisieux et al., 2016). By manipulating Rab10 expression and activity in hippocampal neurons, as well as analysing the axonal dynamics of Rab10 organelles, we have explored its ability to regulate the sorting of TrkB to the retrograde axonal transport pathway and respond to increasing concentrations of BDNF, adjusting retrograde signalling on demand.

Our results unravel a novel role for Rab10 in regulating the sorting of internalised TrkB receptors to the retrograde axonal transport pathway. This function appears to be necessary not only for efficient trafficking of TrkB from axons to soma, but also for the propagation of neurotrophic signalling from distal sites to the nucleus, as shown by the decrease of BDNF-induced CREB activation upon Rab10 knockdown (Figure 2). CREB is a transcription factor supporting neuronal survival and differentiation, which is activated by phosphorylation downstream Akt and MAPK signalling (Wang et al., 2018). Some of the better characterised early response genes to neurotrophic factors (e.g., Egr1, Egr2, Arc, and cFos) are transcriptional targets of CREB, which is also required for BDNF-induced dendritic branching (Esvald et al., 2020; González-Gutiérrez et al., 2020; Kwon et al., 2011). Therefore, CREB phosphorylation is one of the best proxies for global responses to neurotrophic signalling. Long-distance activation of CREB has been reported from distal axons and dendrites, and the endosomal trafficking of phosphorylated TrkB and signalling interactors has been shown to play a crucial role in propagating neurotrophin signalling from the periphery to the nuclear pCREB (Cohen et al., 2011; Riccio et al., 1997; Watson et al., 1999). In our study, we found that Rab10 expression was critical for maintenance and survival of differentiated neurons since its downregulation for 48 hr led to a significant decrease in neuronal density (Figure 1). Similar effects have been reported upon overexpression of dominant-negative mutants of Rab5, the GTPase mediating the formation of early endosomes, but not for Rab11, which controls the recycling of receptors to the plasma membrane (Lazo et al., 2013; Moya-Alvarado et al., 2018), suggesting that these distinct arms of the endosomal network differentially impact on neuronal homeostasis.

Acting as a highly specialised network, Rab GTPases are master regulators of specific membrane trafficking events in eukaryotic cells (Stenmark, 2009). Rab10 is one of the few exceptions to this rule, and during the last 30 years, it has been associated to multiple trafficking pathways, including polarised exocytosis from early endosomes, exocytosis in adipocytes and neurons, endoplasmic reticulum dynamics, and the formation of tubular endosomes, to cite but a few (Chua and Tang, 2018). This multiplicity of functions is reflected by the diversity of its interactors and effectors, emphasising the importance of the specific context in which Rab10 operates. Here we have confirmed previous findings showing that Rab10-positives organelles are present in axons of hippocampal neurons and undergo bidirectional transport (Deng et al., 2014). Importantly, in this work we have demonstrated that the balance between anterograde and retrograde transport of Rab10-positive organelles is regulated by BDNF, indicating the ability of Rab10 to specifically respond to extracellular cues in a signalling context. A similar function of Rab10 balancing anterograde and retrograde transport has been shown to be required for correct dendritic patterning in Drosophila (Taylor et al., 2015).

We hypothesised that the differential recruitment of members of the kinesin superfamily of anterograde motors could explain a rapid change in the directionality of Rab10 organelles. Given that many kinesins distribute preferentially to distinct neuronal compartments (Hirokawa and Tanaka, 2015), we focused on two kinesins that have been found to be predominant in axons, KIF5B and KIF13B (Yang et al., 2019). We found that KIF13B, but not KIF5B, increased its relative abundance in axonal Rab10-positive domains (Figure 6a–f), which is in line with the recent evidence indicating a direct interaction between Rab10 and KIF13A and B, via a Rab-binding domain (RBD)-homology domain (Etoh and Fukuda, 2019). Moreover, when we used immunoprecipitation to investigate the interaction of KIF13B and Rab10, we found that their binding significantly increases in the presence of BDNF (Figure 6g and h). Interestingly, KIF13B and other members of the kinesin-3 family have been shown to yield super processive motion when acting as dimers (Soppina et al., 2014), helping to explain how even a relatively small increase in the recruitment of KIF13B onto axonal Rab10-positive organelle can trigger a rapid change in their transport directionality. Together with an increase of the recruitment of KIF13B and other kinesins, Rab10 effectors can also regulate the motor activity of cytoplasmic dynein (Taylor et al., 2015) or mediate the interaction with axonal myosins (Liu et al., 2013; Welz and Kerkhoff, 2019), where specific contribution to directionality and processivity of these organelles will require further exploration.

Although the main focus of this work has been demonstrating a novel role of Rab10 in the retrograde propagation of neurotrophic signalling, the recruitment of KIF13B onto Rab10-positive organelles is an important finding to start disentangling the mechanisms that control the BDNF-dependent switch between retrograde and anterograde transport. For example, the activity of Rab10 is known to be controlled by PI3K-Akt, a canonical BDNF/TrkB signalling pathway. In adipocytes and muscle cells, Rab10 is known to regulate the plasma membrane delivery of the glucose transporter GLUT4 in response to insulin, where activation of Akt leads to phosphorylation of the Rab GAP Akt substrate of 160 kDa (AS160). Rab10 associated to GLUT4-containing endosomes is kept inactive by AS160 until Akt signalling releases the brake and promotes fusion with the plasma membrane (Sano et al., 2007).

However, two key observations suggest that directionality of Rab10 organelles in the axon does not depend uniquely on Rab10 activity. First, both anterograde and retrograde organelles have membrane-bound Rab10 (Figure 5), which is generally accepted to be its GTP-bound active form. Second, we observed that the constitutively active Rab10^Q68L mutant is transported predominantly in the retrograde direction in neurons depleted of BDNF (see Figure 5—figure supplement 1). Altogether, these findings indicate that whilst the GTP-bound conformation of Rab10 is necessary to drive its binding to the membrane of axonal organelles, this alone is not sufficient to determine the direction of transport. Signalling molecules associated to the membrane of the moving endosome are likely to be key defining its direction and processivity, as exemplified in Figure 5—video 2, which shows an anterograde Rab10-positive carrier running next to a stationary organelle, partially merging and continue moving together.

The LRRK2-dependent phosphorylation of Rab10 in the highly conserved switch II region has been proposed to affect its GTP/GDP cycle as well as its ability to bind effectors (Pfeffer et al., 1995; Xu et al., 2021). Moreover, this phosphorylation site has been shown to regulate the interaction of Rab10 with JIP3 and JIP4 (Waschbüsch et al., 2020), which are adaptors for the plus-end-directed microtubule-dependent motor kinesin-1 (Cockburn et al., 2018; Isabet et al., 2009). Interestingly, JIP3 has been shown to mediate the anterograde transport of TrkB in neurons and, by that mechanism, to enhance BDNF signalling (Huang et al., 2011; Sun et al., 2017). However, preliminary experiments showed that JIP3 and JIP4 association to Rab10 organelles is extremely low in hippocampal neurons and does not respond to BDNF stimulation (Figure 6—figure supplement 2). LRRK2-phosphorylated Rab10 has been also found to recruit myosin Va (Dhekne et al., 2021), providing other candidates for regulation of axonal trafficking. On the other hand, positioning of Rab10-positive membranes has been recently shown to determine their phosphorylation by LRRK2, suggesting that trafficking and composition of these organelles can be mutually regulated (Kluss et al., 2022). Whether LRRK2-mediated phosphorylation of Rab10 modulates the interaction with KIF13B is part of our ongoing research efforts and will not be discussed here in detail; however, it is worth mentioning that all three Rab10, KIF13B, and LRRK2 have been implicated in the formation of tubular endosomes (Bonet-Ponce et al., 2020; Etoh and Fukuda, 2019). Among the most interesting candidates linking BDNF-signalling and LRRK2 activity is Vps35, a component of the retromer complex that has been shown to modulate LRRK2 (Mir et al., 2018) and is recruited by TrkB binding to SorLA (Rohe et al., 2013), a sortilin family member. On the other hand, activation of Akt has been shown to compensate impairments of the insulin-stimulated GLUT4 trafficking associated with LRRK2 deficiency (Funk et al., 2019), opening the possibility that other downstream kinases could regulate Rab10 by LRRK2-independent mechanisms.

Once internalised, axonal TrkB reaches early endosomes, from where it can either recycle back to the plasma membrane, thus fine-tuning the response of nerve terminals to BDNF (reviewed in Andreska et al., 2020) or undergo sorting to the retrograde axonal transport route, propagating neurotrophic signals to the soma (Deinhardt et al., 2006; Ha et al., 2008; Zhou et al., 2012). Given that Rab10 downregulation decreased retrograde transport of TrkB and stimulation with BDNF promoted anterograde transport of Rab10, we reasoned that delivery of Rab10 to axon terminals facilitated the sorting of TrkB to retrogradely transported organelles. We demonstrated that Rab10DN expression increases the accumulation of internalised TrkB in early endosomes without significantly affecting recycling (Figure 7), suggesting that the pool of TrkB receptors available for local recycling and axonal transport are spatially segregated in the early endosome membrane, and thus indicating that functional Rab10 aids the exit of TrkB from early endosomes and its sorting to distinct axonal retrograde organelles.

When overexpressed, Rab10 is found at detectable levels in retrograde signalling endosomes positive for TrkB or p75^NTR (Figure 4). An interesting observation is that only p75 receptors are present in Rab10-containing anterograde organelles, which bears the question on the role of the anterograde delivery of p75^NTR to distal axons. In sympathetic neurons, it has been shown that p75^NTR is rapidly mobilised to the plasma membrane upon stimulation with NGF via activation of Arf6 (Hickman et al., 2018), a small GTPase that has been shown to share common organelles with Rab10 in Caenorhabditis elegans (Shi and Grant, 2013).

At endogenous levels of Rab10, however, when we analysed triple co-localisation of internalised H_CT and TrkB with endogenous Rab10, we found that the absolute amount of retrograde TrkB associated to Rab10 organelles remains low (Figure 3e), suggesting that this interaction is transient. This is in line with previous evidence showing that in MDCK cells, Rab10 mediates transport from early endosomes to a polarised trafficking route (Babbey et al., 2006). Moreover, in C. elegans, Rab10 is recruited to early endosomes where it downregulates Rab5, helping to select cargoes for delivery to recycling endosomes (Liu and Grant, 2015). According to this model, the transfer of TrkB from a stationary early endosome to a retrograde carrier would be preceded by a local increase of Rab10. In Figure 8b, we show an example of a live-cell imaging experiment in which a TrkB-positive endosome makes the transition from stationary to retrograde. We show the level of EGFP-Rab10 during the stationary phase (red), in the transition phase immediately preceding movement (yellow), and during processive retrograde transport (green). Crucially, Rab10 is recruited to this TrkB-positive axonal organelle few seconds before it starts moving retrogradely, strengthening the validity of our working model (Figure 8).

Figure 8

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Rab10 has been shown to participate in the biogenesis of tubular endosomes in mammalian cells (Etoh and Fukuda, 2019) and regulates endosomal phosphatidylinositol-4,5-bisphosphate in C. elegans, suggesting that this small GTPase modulates the membrane recruitment of factors altering membrane curvature and budding (Shi and Grant, 2013). During our live-cell imaging experiments, we observed Rab10-positive tubular organelles moving rapidly into proximal neurites, confirming that these structures are also generated in hippocampal neurons (Figure 5—video 3). In addition, it has been shown that snapin, an adaptor for cytoplasmic dynein recruitment to TrkB-signalling endosomes (Zhou et al., 2012), is also phosphorylated by LRRK2 (Yun et al., 2013), opening the possibility that Rab10 membranes constitute a specialised sorting domain. Interestingly, one of the well-characterised roles of KIF13B in the brain is the transport of phosphatidylinositol-3,4,5-biphosphate via its interactor centaurin-alpha (Hammonds-Odie et al., 1996), which is essential for axon specification (Horiguchi et al., 2006). Further research on the composition and cargo content of Rab10 organelles in neurons is therefore warranted.

Our data suggests that Rab10 regulates the amount of internalised TrkB that is sorted to retrograde signalling endosomes in response to the concentration of BDNF at axon terminals. Since BDNF is known to be released post-synaptically as a function of neuronal activity (Matsuda et al., 2009), retrograde neurotrophic signalling from the axon terminal is a substantial feedback mechanism regulating growth and survival, and therefore, ensuring that active circuits are preserved. To keep this feedback signal meaningful, any change in the availability of BDNF at the synapse must translate into proportional changes in the intensity of the signal arriving at the soma. We propose that Rab10-positive membranes deliver crucial components of the sorting machinery on demand. At steady state, the anterograde and retrograde flow of Rab10 compartments is in equilibrium (Figure 8; low BDNF). Further decrease in BDNF concentration makes retrograde transport of Rab10 carriers predominant, as observed in live-cell imaging experiments performed in neurons treated with anti-BDNF blocking antibodies (Figure 4; no BDNF). In contrast, adding BDNF reverts the directional bias to anterograde (Figure 8; high BDNF), which allows the delivery of appropriate levels of the sorting machinery to nerve terminals, thus increasing the efficiency of TrkB retrograde transport.

An independent example of anterograde delivery of components for the sorting of retrograde signalling molecules has been hypothesised for the bone-morphogenetic protein (BMP) pathway in Drosophila motor neurons. In this work, Khc-73, the fly orthologue of KIF13B, has been shown to regulate BMP sorting from early endosomes at the neuromuscular junction (Liao et al., 2018). This suggests that the proposed mechanism is evolutionary conserved in different neuronal types, increasing its potential as a therapeutic target for pathologies in which neurotrophic signalling from distal axons is impaired.

Little is known about the specific sorting machinery required for the biogenesis of signalling endosomes. Endophilins A1 and A3 have been shown to regulate the trafficking of TrkB across early endosomes and mediate survival signalling (Burk et al., 2017; Fu et al., 2011). Interestingly, endophilin A1 as well as Rab10 are known LRRK2 substrates, opening the possibility of both being found on the same organelle (Matta et al., 2012). Moreover, KIF13B has also been found to be enriched in early endosomes (Bentley et al., 2015). The characterisation of the sorting machinery delivered to axonal terminals by Rab10-positive carriers will be crucial to understand not only how this mechanism allows coordination between local signalling and global neuronal responses, but also how this process may fail in neurodegeneration. In this light, promoting the delivery of Rab10 organelles to nerve terminals may be explored as an novel therapeutic strategy for diseases in which the endolysosomal system is overloaded or dysfunctional, such as Alzheimer’s disease (Van Acker et al., 2019; Xu et al., 2018), or to increase the ability of axons to respond to trophic factors during regeneration.

Source tables for all the data in the manuscript have been submitted as a supplementary file (source data files 1-7).

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Author details

1. Oscar Marcelo Lazo

   1. Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
   2. UK Dementia Research Institute at UCL, London, United Kingdom

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   oscar.lazo@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4542-482X

2. Giampietro Schiavo

   1. Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
   2. UK Dementia Research Institute at UCL, London, United Kingdom

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Project administration, Writing – review and editing

   For correspondence

   giampietro.schiavo@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4319-8745

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