Function of Meteorins in commissural axon guidance – MetAxon

In most animal species characterized by an almost perfect symmetry along the anteroposterior body axes, commissural axons connect neurons on the left and right side of the nervous system. This communication at the level of the two brain hemispheres and the two sides of the spinal cord is necessary for a series of complex function, including binocular vision, coordinated locomotor movements, and sound direction localization. In humans, the balance of commissural and non-commissural axons is essential to CNS physiology and to the integration of sensory stimuli/inputs. Abnormal axon midline crossing during development causes a whole range of neurological disorders ranging from congenital mirror movements to a severe impairment of binocular vision such as in albino patients. Partial or complete corpus callosum agenesis are some of the most common brain malformations in children with variable neurological outcomes.
Understanding the cellular and molecular mechanisms guiding commissural axons to the midline of the nervous system has been a central question for developmental neurobiologists. Studies in vertebrates and invertebrates identified evolutionary conserved proteins that attract commissural axons to the midline. This process is remarkable in that crossing axons are attracted to the midline and then expelled from it the by repulsive molecules after reaching it. Thus, in addition to being a developmental paradigm, commissures also represent a powerful model for understanding the mechanisms underlying neuronal network formation, brain plasticity and axonal regeneration. Despite extensive studies in the past three decades, mounting evidence suggests that the molecular repertoire for midline guidance is more diverse than initially envisaged at not fully understood.


In the proposed program, the two partners (Dr Chédotal, Coordinator and partner 1, and Dr Del Bene, Partner 2) will exploit their complementary expertise in developmental neurobiology to investigate the function of a new family of secreted proteins, the Meteorins, during CNS development.

Our preliminary results show that in zebrafish and mouse, meteorins are expressed in the embryo at the level of the CNS midline crossed by commissural axons during development.
Our main objectives are:
1) To alter the expression of meteorins in mouse, chick and zebrafish to assess their function in vivo. We will also study their activity in vitro on commissural axon outgrowth and neuronal migration.
2) We will use proteomics to identify meteorin receptor(s) and signaling pathway(s).

This project should lead to the identification of novel therapeutic targets for the treatment of neurological diseases and brain injury. It should also improve our understanding of vertebrate brain evolution and it will provide a significant advancement to our understanding of brain wiring control and neural circuit formation.