Molecular mechanisms orchestrating commissural axon guidance

Commissural neurons ensure the coordination of motor and somatosensory information between halves of the central nervous system. In the caudal part of the CNS, commissural axons, first grow toward the ventral midline, the floor plate, to cross it and reach their final target. The cellular and molecular mechanisms controlling midline crossing have been extensively studied. Ram—n y Cajal, in his neurotropic theory, suggested that floor plate cells could release diffusible factors chemo-attracting commissural axons to the ventral midline. Netrin-1, a protein discovered more than 2 decades ago, is a secreted protein expressed both by floor plate cells and ventricular zone progenitors and with long-range chemoattractive activity in vitro. Today, Netrin-1 is widely accepted as the textbook example of long-range chemoattractive guidance cue. However, our results, challenge this model by proposing a short-range mechanism of action for Netrin-1 during commissural axon guidance. Indeed, we determined that floor plate-derived netrin-1 is dispensable for commissural axon guidance. Instead, ventricular zone-derived netrin-1 is necessary and sufficient to promote the dorso-ventral extension of hindbrain commissural axons and midline crossing. We also confirmed that ventricular zone progenitors are the main Netrin-1 source for ventrally migrating precerebellar neurons. In addition, we observe that in absence of ventricular zone-derived netrin-1, commissural axons and precerebellar neurons cell bodies invade several cranial nerves. This appears to be a cell- autonomous and Dcc-dependent process. This mechanism is not conserved in the spinal cord, where both netrin-1 sources act synergistically to ensure commissural axon guidance and midline crossing. Commissural neurons are diverse and found throughout the nervous system. To analyse the molecular diversity of hindbrain and spinal cord commissural neurons, we used approaches combining mouse genetics and transcriptomics. We are currently working on some novel transcription factors that might play a role in the development of hindbrain and spinal cord commissural neurons.