Genetic factors driving the functional specification of spinal motor neurons

Abstract

Spinal motor neurons which innervate different types of muscle fibers play a pivotal role in controlling body postures and locomotion. Spinal motor neurons can be broadly classified into alpha- and gamma-motor neuron subtypes. Alpha-motor neurons can be further subdivided into fast and slow functional subtypes. It is known that several spatially and temporally orchestrated transcriptional cascades are instrumental in determining and specifying various neuronal subtypes in the neural tube during neurogenesis. However, the factors responsible for determining the specification of functional spinal motor neuron subtypes (alpha versus gamma; slow versus fast) are still unknown. In this study, I performed transcriptome analysis in E18.5 mice to identify the gene expression profiles of functionally distinct motor pools to identify determinants of motor neuron subtype. Through this screen, I identified the orphan nuclear receptor Err2 as a selective marker for gamma-motor neurons. The expression of Err2 paralleled that of the closely related Err3, a previously identified gamma-motor neuron marker. Through novel transposon-mediated gene manipulation in the embryonic chick spinal cord, I found that both Err2 and Err3 are sufficient to promote gamma-motor neuron identity, based on morphological, molecular and initial physiological criteria. Fusion of heterologous transcriptional activation or repression domains further suggested that Err2 and Err3 act as transcriptional activators. My thesis project thereby uncovered first insights into the functional specification of motor neurons, and provided evidence that Err2 and Err3 act as genetically redundant transcription activators that promote the acquisition of gamma-motor neuron identity in subsets of motor neurons.