Molecular control of spinal accessory motor neuron development

Abstract

The ability of the mature vertebrate to orchestrate complex muscle movements requires the formation of highly specific axonal connections between motor neuron (MN) cell bodies and target muscles during development. Several intricate steps are involved in the formation of these connections. First, the combinatorial expression of transcription factors specifies MN subtype identity. These MN subtypes are further defined by the settling position of their cell bodies in the spinal cord into motor columns, and motor pools. Motor axons then travel along a given path within the spinal cord by responding to attractive and repellent guidance cues in the environment, which lead them out of the CNS via appropriate exit points. Once they have exited the CNS, motor axons travel to, and innervate, the appropriate muscle in the periphery. Despite these criteria that allow us to distinguish between MN subtypes, the inclusive set of cues required by subtypes of motor axons to navigate these precise routes remain elusive. The lack of available specific markers for MN subtypes and their axons have contributed to this conundrum. As a first step toward overcoming this limitation, I have identified a monoclonal antibody as a specific marker of a unique population of dorsally exiting motor neurons, referred to as spinal accessory motor neurons (SACMN). Using this marker together with knockout mice lacking particular axon guidance receptor/ligands or transcription factors, I have identified molecules required for distinct stages of SACMN development. Specifically, I show that the transcription factor Gli2 is required for the timely development and outgrowth of SACMN axons, and that the guidance molecule Netrin-1 and its receptor DCC are required for the dorsal migration of SACMN towards the lateral exit point. I further suggest a role for the UNC5 receptors in this Netrin-mediated repulsion of SACMN from the midline. In addition, I examine the role of other major ventral midline guidance systems in SACMN development. Finally, I address the matter of SACMN axon exit from the CNS and delineate a role for the transcription factors Nkx2.9 and Nkx2.2 in this fundamental event. These findings suggest molecular mechanisms that control sequential stages of SACMN development.