RabGDI controls axonal midline crossing by regulating Robo1 surface expression

Neural Development

Esther T Stoeckli³  Beat Kunz³  Tobias Alther³  Marc Debrunner³  Vera Niederkofler¹  Melanie Philipp² 

[1] Department of Genetics, Harvard Medical School, Boston, USA;Institute for Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany;Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, CH, 8057, Switzerland

关键词: Mental retardation gene;    Spinal cord development;    Chicken embryo;    Membrane trafficking;    Slit;    In ovo RNAi;    Axon guidance;   

Others  :  806844
DOI  :  10.1186/1749-8104-7-36

 received in 2012-08-22, accepted in 2012-10-12,  发布年份 2012

【 摘 要 】

Background

Axons navigate to their future synaptic targets with the help of choice points, intermediate targets that express axon guidance cues. Once they reach a choice point, axons need to switch their response from attraction to repulsion in order to move on with the next stage of their journey. The mechanisms underlying the change in axonal responsiveness are poorly understood. Commissural axons become sensitive to the repulsive activity of Slits when they cross the ventral midline of the CNS. Responsiveness to Slits depends on surface expression of Robo receptors. In Drosophila, Commissureless (Comm) plays a crucial regulatory role in midline crossing by keeping Robo levels low on precommissural axons. Interestingly, to date no vertebrate homolog of comm has been identified. Robo3/Rig1 has been shown to control Slit sensitivity before the midline, but without affecting Robo1 surface expression.

Results

We had identified RabGDI, a gene linked to human mental retardation and an essential component of the vesicle fusion machinery, in a screen for differentially expressed floor-plate genes. Downregulation of RabGDI by in ovo RNAi caused commissural axons to stall in the floor plate, phenocopying the effect observed after downregulation of Robo1. Conversely, premature expression of RabGDI prevented commissural axons from entering the floor plate. Furthermore, RabGDI triggered Robo1 surface expression in cultured commissural neurons. Taken together, our results identify RabGDI as a component of the switching mechanism that is required for commissural axons to change their response from attraction to repulsion at the intermediate target.

Conclusion

RabGDI takes over the functional role of fly Comm by regulating the surface expression of Robo1 on commissural axons in vertebrates. This in turn allows commissural axons to switch from attraction to repulsion at the midline of the spinal cord.

【 授权许可】

   
2012 Philipp et al.; licensee BioMed Central Ltd.

【 图 表 】

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