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Histone lysine demethylase JMJD3/KDM6B is required for the establishment of adult hippocampal neurogenesis

ABSTRACT: Mutations in the JMJD3 (KDM6B) chromatin regulator are causally associated with autism spectrum disorder and syndromic intellectual disability, but the neurodevelopmental roles of this histone 3 lysine 27 (H3K27) demethylase are poorly understood. Neural stem cells (NSCs) in the hippocampal dentate gyrus (DG) generate new granule neurons throughout life, and deficits in DG neurogenesis are associated with cognitive and behavioral problems. Here we show that Jmjd3 is required for the establishment of adult neurogenesis in the mouse DG. Conditional deletion of Jmjd3 in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs. While early postnatal mice with Jmjd3-deletion have near normal numbers of DG NSCs, at later stages, Jmjd3-deleted NSCs fail to propagate normally. In addition to the loss of NSCs during postnatal development, neurogenesis from Jmjd3-deleted NSCs is impaired, corresponding to defective neurogenic gene expression. Without Jmjd3, NeuroD2 and Bcl11b(Ctip2) are not properly expressed and exhibit increased levels of H3K27me3, underscoring the role of Jmjd3 in the regulation of transcription for neuronal differentiation. Thus, these data indicate that Jmjd3 plays dual roles in postnatal DG neurogenesis, being critical for the establishment of the NSC pool as well as the differentiation of young DG granule neurons. More broadly, our results suggest a neurodevelopmental link between JMJD3 mutations and hippocampal dysfunction, providing new insights into how mutations in chromatin regulators may contribute to learning disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE73706 | GEO | 2021/04/01

REPOSITORIES: GEO

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Project description:We sought to find molecular signatures of the SGZ cell types, and to characterize the molecular pathways and transcription factor cascades that define the neurogenic niche. We used laser capture microdissection and DNA microarrays to profile gene expression in the inner (SGZ) and outer portions of the dentate gyrus (DG). Since the vast majority of the cells in the DG are mature granule cells, we compared the expression of the inner and outer portions to reveal molecular markers for the less numerous populations of the SGZ. This data set is part of a larger study assessing conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Using a combination of selective SGZ transcriptional profiling with laser microdissection and DNA microarrays as well as in situ hybridization (ISH), we developed an extensive molecular characterization of the mouse SGZ, identifying 367 genes enriched in the SGZ compared to mature granule neurons. These genes displayed a wide range of cellular expression patterns reflecting the cellular milieu of the SGZ, including progenitor and dividing cells, immature granule cells, astrocytes, oligodendrocytes, and GABAergic interneurons. We next used a comparable microarray data set in rhesus monkey that profiled the SGZ across postnatal development to identify genes related to developmentally regulated granule cell neurogenesis. The rhesus monkey SGZ showed highly significant similarity to mouse, whereas network analysis of these data identified SGZ-enriched gene sets with different temporal profiles reflecting differential time-courses for maturation of glia and granule neurons. One neurogenesis-related gene network showed a steady decrease in expression across postnatal rhesus development from birth to adulthood. This temporal pattern is highly correlated with the number of proliferating cells in the dentate gyrus, and the neurogenic transcription factors Sox4 and Sox11 are central hub genes for this gene network. A number of the genes in this network showed a similar postnatal downregulation in mouse, suggesting a general conservation of molecular mechanisms underlying developmental and adult neurogenesis in rodents and primates. Primate data available at: http://www.blueprintnhpatlas.org/ Brains from 10- to 11-week-old C57BL/6 male mice housed in three conditions (no running, 4 days of running, 30 days of running) were sectioned and the dentate gyrus was isolated. For each brain, the inner granule cell layer (containing the subgranular zone) and outer GCL were separated using laser capture microdissection, and RNA from each region was collected and processed as described in the protocols.

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Histone lysine demethylase JMJD3/KDM6B is required for the establishment of adult hippocampal neurogenesis

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