Abstract
BackgroundMammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied.MethodsOur previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates. Here, we examine the expression pattern of all four mouse COE family members (mEbf1-mEbf4) in spinal MNs and employ genetic approaches in both nematodes and mice to investigate their function in axial MN development.ResultsWe report that mEbf1 and mEbf2 are expressed in distinct MN clusters (termed “columns”) that innervate different axial muscles. Mouse Ebf1 is expressed in MNs of the hypaxial motor column (HMC), which is necessary for breathing, while mEbf2 is expressed in MNs of the medial motor column (MMC) that control spinal alignment. Our characterization of Ebf2 knock-out mice uncovered a requirement for Ebf2 in the differentiation program of a subset of MMC MNs and revealed for the first time molecular diversity within MMC neurons. Intriguingly, transgenic expression of mEbf1 or mEbf2 can rescue axial MN differentiation and locomotory defects in nematodes (Caenorhabditis elegans) lacking unc-3, the sole C. elegans ortholog of the COE family, suggesting functional conservation among mEbf1, mEbf2 and nematode UNC-3.ConclusionsThese findings support the hypothesis that genetic programs controlling axial MN development are deeply conserved across species, and further advance our understanding of such programs by revealing an essential role for Ebf2 in mouse axial MNs. Because human mutations in COE orthologs lead to neurodevelopmental disorders characterized by motor developmental delay, our findings may advance our understanding of these human conditions.
Highlights
Mammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles
Ebf1 and Ebf2 are expressed in distinct MN populations that innervate axial muscles Since orthologs of COE family Transcription factor (TF) control aspects of MN differentiation in the nematode C. elegans and the simple chordate C. intestinalis [21], we hypothesized that the function of COE TFs is conserved in mouse MNs
Since orthologs of Ebf2, in nematodes and simple chordates, are required for expression of the highly conserved genes involved in acetylcholine (ACh) biosynthesis, we evaluated the expression of the ACh pathway genes VAChT and Acly by RNA in situ hybridization (ISH) in medial motor column (MMC) neurons of Ebf2 KO embryonic spinal cords (Fig. 2a)
Summary
Mammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. The molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied. The mammalian neuromuscular system is essential for distinct motor behaviors ranging from locomotion and dexterity to basic motor functions, such as breathing and maintenance of spinal alignment [1]. The underlying basis for achieving these diverse outputs lies in the assembly of distinct neuronal circuits dedicated to control (2019) 14:2 A Brachial Thoracic LMC PMC MMC HMC PGC D Ebf mRNA Foxp B
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