The histone demethylase Kdm6b regulates subtype diversification of mouse spinal motor neurons during development

Wenxian Wang,Hyeyoung Cho,Jae W Lee,Soo-Kyung Lee

doi:10.1038/s41467-022-28636-7

Abstract

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.

Highlights

How a single neuronal population diversifies into subtypes with distinct synaptic targets is a fundamental topic in neuroscience whose underlying mechanisms are unclear
Kdm6b mRNA transcripts were upregulated as newborn motor neurons (MNs) emerged from the progenitors in the spinal cord at E10.5, and Kdm6b levels remained higher in neurons than progenitors at E12.5 (Fig. 1a)
The schematics depict the location of neural progenitor cells (NPC) in the ventricular zone and neurons in the mantle zone. b Immunohistochemical analysis with Kdm6b antibody shows that Kdm6b protein was detected in E11.5 control and eliminated in E11.5 Kdm6b-cKO mice

Summary

Introduction

How a single neuronal population diversifies into subtypes with distinct synaptic targets is a fundamental topic in neuroscience whose underlying mechanisms are unclear. 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. LMC differentiates into the two subtypes, medial LMC (LMCm) and lateral LMC (LMCl), which targets the ventral and dorsal limb muscles, respectively It remains unclear if other motor columns subdivide into distinct subgroups. Kdm6a and Kdm6b can be recruited to the specific target genes by associating with their partner TFs and activate the target gene transcription by triggering changes in histone marks and chromatin landscape[29,32] Both Kdm6a and Kdm6b are implicated in neural stem cell generation and neurogenesis[33–37], but their role in neuronal diversification remains unexplored

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