Department of Neurobiology, University of Chicago, Chicago, IL, USA.
Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
Neural Dev. 2019 Jan 18;14(1):2. doi: 10.1186/s13064-018-0125-6.
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. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied.
Our 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.
We 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.
These 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.
哺乳动物运动回路表现出显著的细胞多样性，数以百计的运动神经元 (MN) 亚型支配着数百种不同的肌肉。对肢体肌肉支配 MN 的广泛研究已经开始阐明控制动物运动的遗传程序。相比之下，控制呼吸和脊柱排列的轴向肌肉支配 MN 的发育的分子机制研究甚少。
我们之前的研究表明，Collier/Olf/Ebf (COE) 转录因子 (TF) 家族在轴向 MN 发育中的功能可能从线虫到简单的脊索动物中得到保守。在这里，我们检查了所有四种小鼠 COE 家族成员 (mEbf1-mEbf4) 在脊髓 MN 中的表达模式，并在线虫和小鼠中采用遗传方法研究它们在轴向 MN 发育中的功能。
我们报告说 mEbf1 和 mEbf2 在支配不同轴向肌肉的不同 MN 簇（称为“柱”）中表达。小鼠 Ebf1 在支配呼吸的腹侧运动柱 (HMC) 的 MN 中表达，而 mEbf2 在支配脊柱排列的内侧运动柱 (MMC) 的 MN 中表达。我们对 Ebf2 敲除小鼠的特征描述揭示了 Ebf2 对 MMC MN 亚群分化程序的要求，并首次揭示了 MMC 神经元中的分子多样性。有趣的是，mEbf1 或 mEbf2 的转基因表达可以挽救线虫 (秀丽隐杆线虫) 中 UNC-3 缺失时的轴向 MN 分化和运动缺陷，UNC-3 是 COE 家族在秀丽隐杆线虫中的唯一直系同源物，这表明 mEbf1、mEbf2 和线虫 UNC-3 之间存在功能保守性。
这些发现支持了这样的假设，即控制轴向 MN 发育的遗传程序在物种间是深度保守的，并通过揭示 Ebf2 在小鼠轴向 MN 中的重要作用，进一步推进了我们对这些程序的理解。由于 COE 同源物的人类突变导致以运动发育迟缓为特征的神经发育障碍，我们的发现可能有助于我们理解这些人类疾病。
