Department of Biological Sciences, College of Arts and Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, 14260, USA.
Computational Biology Program, School of Medicine, Oregon Health & Science University, Portland, OR, 97239, USA.
Nat Commun. 2022 Feb 17;13(1):958. doi: 10.1038/s41467-022-28636-7.
How a single neuronal population diversifies into subtypes with distinct synaptic targets is a fundamental topic in neuroscience whose underlying mechanisms are unclear. Here, we show that the histone H3-lysine 27 demethylase Kdm6b regulates the diversification of motor neurons to distinct subtypes innervating different muscle targets during spinal cord development. In mouse embryonic motor neurons, Kdm6b promotes the medial motor column (MMC) and hypaxial motor column (HMC) fates while inhibiting the lateral motor column (LMC) and preganglionic motor column (PGC) identities. Our single-cell RNA-sequencing analyses reveal the heterogeneity of PGC, LMC, and MMC motor neurons. Further, our single-cell RNA-sequencing data, combined with mouse model studies, demonstrates that Kdm6b acquires cell fate specificity together with the transcription factor complex Isl1-Lhx3. Our study provides mechanistic insight into the gene regulatory network regulating neuronal cell-type diversification and defines a regulatory role of Kdm6b in the generation of motor neuron subtypes in the mouse spinal cord.
单一神经元群体如何分化为具有不同突触靶点的亚型是神经科学的一个基本课题，其潜在机制尚不清楚。在这里，我们表明，组蛋白 H3-赖氨酸 27 去甲基酶 Kdm6b 调节脊髓发育过程中运动神经元向不同的肌肉靶区分化为不同亚型。在小鼠胚胎运动神经元中，Kdm6b 促进内侧运动柱（MMC）和轴下运动柱（HMC）命运，同时抑制外侧运动柱（LMC）和节前运动柱（PGC）特征。我们的单细胞 RNA 测序分析揭示了 PGC、LMC 和 MMC 运动神经元的异质性。此外，我们的单细胞 RNA 测序数据与小鼠模型研究相结合，表明 Kdm6b 与转录因子复合物 Isl1-Lhx3 一起获得细胞命运特异性。我们的研究为调节神经元细胞类型多样化的基因调控网络提供了机制见解，并定义了 Kdm6b 在小鼠脊髓运动神经元亚型产生中的调节作用。
