Molecular principles of motor neuron diversity

Two distinct gene regulatory strategies generate motor neuron diversity in C.elegans
Paschalis Kratsios¹, Sze Yen Kerk², Catarina Catela¹, and Oliver Hobert²
1: Department of Neurobiology, University of Chicago, Chicago, IL 60637
2: Department of Biological Sciences, HHMI, Columbia University, New York, NY 10032

A central goal of developmental neurobiology is to decipher the molecular underpinnings of neuronal diversity. To study this problem, we set to reveal the mechanistic basis for the diversification of motor neuron classes in the nematode C. elegans. Cholinergic motor neurons in the ventral nerve cord (VNC) of C. elegans share common traits and these traits are directly activated by the EBF/COE-like transcription factor UNC-3. Through forward genetic screens, we find that the diversification of these UNC-3/EBF-dependent cholinergic motor neurons into distinct classes, each characterized by unique patterns of effector gene expression (e.g. motor neuron class-specific ion channels, signaling molecules and neurotransmitter receptors), is controlled by distinct sets of phylogenetically conserved, motor neuron class-specific transcriptional repressors. These repressor proteins prevent UNC-3/EBF from activating motor neuron class-specific genes in specific motor neuron subsets via discrete cis-regulatory elements. However, this repressor strategy does not entirely explain how the expression of UNC-3/EBF-dependent effector genes is activated in specific motor neuron classes. We therefore hypothesized that UNC-3 requires additional factors to generate motor neuron diversity and indeed found that the Hox spatial selector proteins synergize with UNC-3/EBF by employing a region-based strategy along the VNC to activate the expression of motor neuron-class specific effector genes. Intriguingly, Hox and unc-3 orthologs are coexpressed in mouse MNs along the spinal cord, suggesting that this intersectional, region-based regulatory principle may be conserved across phylogeny. Taken together, our results reveal two distinct gene regulatory strategies that sculpt motor neuron class-specific gene expression to generate neuronal diversity.  

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