CRMP4-mediated fornix development involves semaphorin-3E signaling pathway
- Univ. Grenoble Alpes, Inserm, U1216, CEA, Grenoble Institut Neurosciences, France
- Univ. Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, France
- McGill University, Canada
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 2, Figure 4, Figure 5, Figure 6 , Figure 7, Figure 8, Figure 9, Figure 10 and supplementary File 1
Article and author information
Author details
Muriel Jacquier-Sarlin
Jean-Christophe Deloulme
Funding
Agence Nationale de la Recherche (2010- Blanc-120201 CBioS)
- Christophe Bosc
Agence Nationale de la Recherche (2017-CE11-0026 MAMAs)
- Annie Andrieux
The funder had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The study protocol was approved by the local animal welfare committee (Comité Local GIN, C2EA-04 - APAFIS number 8303-2016060110523424) and complied with EU guidelines (directive 2010/63/EU). Every precaution was taken to minimize the number of animals used and stress to animals during experiments.
Copyright
© 2021, Boulan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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CRMP4-mediated fornix development involves semaphorin-3E signaling pathway
eLife 10:e70361.
https://doi.org/10.7554/eLife.70361
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