CRMP4-mediated fornix development involves Semaphorin-3E signaling pathway

Abstract

Neurodevelopmental axonal pathfinding plays a central role in correct brain wiring and subsequent cognitive abilities. Within the growth cone, various intracellular effectors transduce axonal guidance signals by remodeling the cytoskeleton. Semaphorin-3E (Sema3E) is a guidance cue implicated in development of the fornix, a neuronal tract connecting the hippocampus to the hypothalamus. Microtubule-Associated Protein 6 (MAP6) has been shown to be involved in the Sema3E growth-promoting signaling pathway. In this study, we identified the Collapsin Response Mediator Protein 4 (CRMP4) as a MAP6 partner and a crucial effector in Sema3E growth-promoting activity. CRMP4-KO mice displayed abnormal fornix development reminiscent of that observed in Sema3E-KO mice. CRMP4 was shown to interact with the Sema3E tripartite receptor complex within Detergent-Resistant Membrane (DRM) domains, and DRM domain integrity was required to transduce Sema3E signaling through the Akt/GSK3 pathway. Finally, we showed that the cytoskeleton-binding domain of CRMP4 is required for Sema3E's growth-promoting activity, suggesting that CRMP4 plays a role at the interface between Sema3E receptors, located in DRM domains, and the cytoskeleton network. As the fornix is affected in many psychiatric diseases, such as schizophrenia, our results provide new insights to better understand the neurodevelopmental components of these diseases.

Plexin B3 guides axons to cross the midline in vivo

“…Besides these small molecules, Plexins can also interact with other molecules such as collapsin-response mediator proteins (CRMPs). CRMP4 has been found to interact with Sema3E tripartite receptor complex and its cytoskeleton-binding domain is required for Sema3E’s axon growth-promoting activity ( Boulan et al, 2021 ). We have demonstrated that CRMP4 is critical for zebrafish retinal axon growth and guidance ( Liu et al, 2018 ).…”

Microtubule remodelling as a driving force of axon guidance and pruning

“…MAP6 (also known as STOP) is a versatile regulator of neuronal connectivity that was first identified as a MT stabilising protein required for MT protection against cold-and nocodazole-induced depolymerisation [130,131]. Neuroanatomical analysis of MAP6 knockout brains reveals substantial hypoplasia of several commissures and axonal tracts, including the absence of the post-commissural part of the fornix [132][133][134]. Regarding this latter phenotype, MAP6 is required for the Sema3E-induced axon outgrowth of subicular neurons (i.e.…”