Genetic Dissection of the Function of Hindbrain Axonal Commissures

Nicolas Renier,Marc Tessier-Lavigne,Paul Avan,Alain Chédotal,Chris I De Zeeuw,Fabrice Giraudet,Aleksandra Badura,Martijn Schonewille,William A Harris

doi:10.1371/journal.pbio.1000325

Abstract

Author SummaryCoordination of the left and right sides of the body requires the action of neurons whose axons cross the nervous system midline. The precise contributions of “commissural” neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels. A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations. This led to disruption of specific commissures in the sensory, motor, and sensorimotor systems, and resulted in severe but specific functional deficits. Surprisingly, although rerouted axons do not cross the midline, they still project to their appropriate neuronal targets, suggesting that midline crossing is not required to complete the axonal guidance program of those neurons. Moreover, some of the mouse lines represent good models for human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS), which is characterized by deficits in coordinated eye movements. This study links defects in commissural axon guidance with specific and dramatic behavioral phenotypes.

Highlights

At all levels of vertebrate nervous systems, axons cross the midline to form commissural projections [1,2]
The precise contributions of ‘‘commissural’’ neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels
A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations

Summary

Introduction

At all levels of vertebrate nervous systems, axons cross the midline to form commissural projections [1,2]. In the visual system and the corpus callosum in the neocortex, the physiological importance of brain commissures is well established in large part due to the ‘‘split-brain’’ studies of Roger Sperry [3] and others. The function of commissural projections in the hindbrain and spinal cord has been more difficult to assess. Ablating specific commissures in the hindbrain has proved to be difficult [4]. No mutant has been created in which these connections are disrupted in a region-specific manner. The function of specific commissures in a variety of hindbrain systems remains uncertain

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