Abstract
A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5–Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus.
Highlights
The neural circuits that govern locomotor behaviors rely on the establishment of orderly sets of connections between motor neurons (MNs) and their peripheral and central synaptic targets
The establishment of connections between motor neurons and limb muscles is mediated through the actions of genes encoding Hox proteins, a large family of transcription factors conserved amongst all metazoans
We have found that members of the Hox6 gene paralog group (Hoxa6, Hoxc6, and Hoxb6) contribute to diverse aspects of motor neuron subtype differentiation
Summary
The neural circuits that govern locomotor behaviors rely on the establishment of orderly sets of connections between motor neurons (MNs) and their peripheral and central synaptic targets. A critical and early step in the emergence of locomotor circuitry is the selection of specific muscle targets by a diverse array of MN subtypes. MNs that project axons to common peripheral targets are organized into columns longitudinally arrayed along the rostrocaudal axis of the spinal cord [1,2]. MNs that project into the limb are contained within the lateral motor columns (LMCs), which are generated at brachial and lumbar levels of the spinal cord. LMC neurons subsequently segregate into medial and lateral divisions, a program that dictates whether motor axons project into dorsal or ventral compartments of the limb mesenchyme [3,4]. MNs must acquire a sufficient level of subtype diversity to ensure the appropriate muscle connectivity required for the emergence of coordinate locomotor behavior
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