Sensory Axon Growth Requires Spatiotemporal Integration of CaSR and TrkB Signaling

Abstract

Neural circuit development involves the coordinated growth and guidance of axons. During this process, axons encounter many different cues, but how these cues are integrated and translated into growth is poorly understood. In this study, we report that receptor signaling does not follow a linear path but changes dependent on developmental stage and coreceptors involved. Using developing chicken embryos of both sexes, our data show that calcium-sensing receptor (CaSR), a G-protein-coupled receptor important for regulating calcium homeostasis, regulates neurite growth in two distinct ways. First, when signaling in isolation, CaSR promotes growth through the PI3-kinase-Akt pathway. At later developmental stages, CaSR enhances tropomyosin receptor kinase B (TrkB)/BDNF-mediated neurite growth. This enhancement is facilitated through a switch in the signaling cascade downstream of CaSR (i.e., from the PI3-kinase-Akt pathway to activation of GSK3␣ Tyr279). TrkB and CaSR colocalize within late endosomes, cotraffic and coactivate GSK3, which serves as a shared signaling node for both receptors. Our study provides evidence that two unrelated receptors can integrate their individual signaling cascades toward a nonadditive effect and thus control neurite growth during development.

New insights into the molecular mechanisms of axon guidance receptor regulation and signaling

“…The authors hypothesized that GSK-3 cycles between active and inactive states. Supporting this idea, phosphorylation of tau, a downstream target of GSK-3, shows a cycling behavior when CasR and TrkB are coactivated but not when CasR is activated alone (Markworth et al, 2019). Since phosphorylation of tau can affect its ability to promote MT assembly (Lindwall & Cole, 1984), cycling between tau dephosphorylation and phosphorylation can potentially induce successive rounds of microtubule assembly and disassembly to regulate neurite outgrowth.…”

“…6B). Different guidance receptors internalized into a common vesicle can elicit signaling cascades that interact to generate an entirely novel output (Markworth et al, 2019). For example, CasR and TrkB can interact in a ligand-independent manner, and upon coactivation in chick sensory neurons, CasR and TrkB colocalize and co-traffic in Rab7-positive late endosomes.…”

Held Up in Traffic—Defects in the Trafficking Machinery in Charcot-Marie-Tooth Disease

“…Dynein interacts with cargo via a dynein/dynactin complex involving p150glued. Deregulation in microtubule assembly and disassembly has been shown to affect axonal growth (Markworth et al, 2019). Importantly, neurotrophic signaling can affect microtubule stability (Goold and Gordon-Weeks, 2003).…”

The calcium-sensing receptor (CaSR) regulates zebrafish sensorimotor decision making via a genetically defined cluster of hindbrain neurons

“… 19 CaSR is highly conserved in vertebrates 20 and has been extensively studied for its role in maintaining serum calcium homeostasis. 21 – 23 CaSR also contributes to nervous system development 24 – 27 and plays an acute role in nervous system function including in synaptic transmission. 28 , 29 In a wide array of cell types including neurons and astrocytes, 30 CaSR facilitates acute adaptation to changing extracellular calcium concentrations.…”