Calsyntenin 1-mediated trafficking of axon guidance receptors regulates the switch in axonal responsiveness at a choice point

Abstract

Axon guidance at choice points depends on the precise regulation of guidance receptors on the growth cone surface. Upon arrival at the intermediate target or choice point, a switch from attraction to repulsion is required for the axon to move on. Dorsal commissural (dI1) axons crossing the ventral midline of the spinal cord in the floor plate represent a convenient model for the analysis of the molecular mechanism underlying the switch in axonal behavior. We identified in chick a role for calsyntenin 1 in the regulation of vesicular trafficking of guidance receptors in dI1 axons at choice points. In cooperation with RabGDI, calsyntenin 1 shuttles Rab11-positive vesicles containing Robo1 to the growth cone surface in a precisely regulated manner. By contrast, calsyntenin 1-mediated trafficking of frizzled 3, a guidance receptor in the Wnt pathway, is independent of RabGDI. Thus, tightly regulated insertion of guidance receptors, which is required for midline crossing and the subsequent turn into the longitudinal axis, is achieved by specific trafficking.

The CTNNBIP1-CLSTN1 fusion transcript regulates human neocortical development

“…The dysregulated gene expression network for Wnt signaling might have caused disordered neurogenesis patterns. Given that the parental gene product CLSTN1 regulates trafficking of a variety of molecules (Alther et al, 2016;Vogt et al, 2001), it is possible that CTCL fusion may facilitate localization of ICAT activity to subcellular domains. These possibilities await further investigation.…”

Synaptic-like Vesicles Facilitate Pioneer Axon Invasion

“…In addition, exocytic trafficking of vesicles at the growth cone has long been known to occur throughout axon navigation. Specifically, growth cones use exocytic machinery to control the extracellular concentration of trophic factors, guidance cues, matrix metalloproteinases (MMPs), cell adhesion proteins, and guidance cue receptors [4][5][6]. For example, super-resolution images of navigating growth cones in culture have identified MMP14 expression at the growth cone, but the mechanism of MMP14 addition to the growth cone was not interrogated [7].…”

Activation of the CaMKII-Sarm1-ASK1 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria

“…Calsyntenin/CASY-1 has been shown to function as a kinesin adaptor that transports vesicular and protein cargoes from the neuronal cell body to the distal axon (Konecna et al, 2006). For example, mammalian calsyntenin-1 can mediate the anterograde transport of APP (Ludwig et al, 2009) and axon guidance receptors such as Robo1 and frizzled 3 (Alther et al, 2016). In C. elegans, CASY-1 mediates the translocation of a specific insulin receptor isoform, DAF-2C, from the soma to the distal axon in ASE neurons during taste avoidance learning (Ohno et al, 2014), and also modulates the transport of synaptic vesicles in GABAergic neurons (Thapliyal et al, 2018).…”

“…The three human calsyntenin proteins (CLSTN1-3) regulate diverse neuronal functions. For example, CLSTN1 mediates trafficking of NMDA receptors (Ster et al, 2014) and axon guidance receptors (Alther et al, 2016), and regulates axon branching (Ponomareva et al, 2014) and microtubule polarity (Lee et al, 2017). CLSTN2 is involved in learning and memory (Lipina et al, 2016;Preuschhof et al, 2010).…”