The Robo3 receptor controls midline crossing by axons. Deleting Robo3 in specific commissural neurons with a conditional knockout reveals their contribution to sensory and motor integration, and models human neurological conditions.
In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre;Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes.
Coordination 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.