Chromatin Regulator Kdm6b is Essential for Establishing and Maintaining Neural Stem Cells in the Mouse Hippocampus

Core Concepts

Kdm6b, a chromatin regulator, is required for the establishment and long-term maintenance of neural stem cells in the mouse hippocampal dentate gyrus.

Abstract

The study investigates the role of the chromatin regulator Kdm6b in the establishment and maintenance of neural stem cells (NSCs) in the mouse hippocampal dentate gyrus (DG). Key findings: Kdm6b is expressed in the developing DG during postnatal NSC establishment. Conditional deletion of Kdm6b in the developing DG results in an adult hippocampus that is devoid of NSCs, leading to defective hippocampal-dependent behaviors. Kdm6b-deletion causes precocious neuronal differentiation of embryonic DG precursor cells, preventing the proper establishment of the adult NSC population. Single-cell RNA sequencing reveals that Kdm6b-deleted NSCs have a disrupted transcriptomic signature of stem cell maintenance, with downregulation of key NSC maintenance genes. Acute deletion of Kdm6b in adult DG NSCs leads to their precocious differentiation and depletion of the NSC pool. The histone demethylase activity of KDM6B corresponds to the chromatin state that underlies NSC maintenance, with increased H3K27me3 levels at regulatory regions of downregulated NSC maintenance genes. These results highlight the critical role of Kdm6b in regulating the establishment and long-term maintenance of the adult hippocampal NSC population, which is essential for lifelong neurogenesis and hippocampal-dependent cognitive functions.

Stats

Kdm6b-deleted DG exhibited a 28% increase in intermediate progenitors and a 43% increase in neuroblasts compared to controls at 10 days post tamoxifen administration. There was a 25% reduction in adult NSCs in Kdm6b-deleted DG compared to controls at 30 days post tamoxifen administration.

Quotes

"Without Kdm6b, DG NSCs undergo precocious neuronal differentiation, depleting the NSC population, which produces an adult DG essentially devoid of neurogenesis." "The perturbation in the transcriptome that results from the deletion of Kdm6b appears to drive stem cells into a more differentiated state." "These data illustrate the critical role that Kdm6b plays in adult DG neurogenesis, which may help understand how mutations in this chromatin regulator result in cognitive disorders in human patients."

Key Insights Distilled From

Chromatin regulator Kdm6b is required for the establishment and maintenance of neural stem cells in mouse hippocampus

by Gil,E., Hong... at www.biorxiv.org 02-21-2024

https://www.biorxiv.org/content/10.1101/2024.02.20.581302v1

Deeper Inquiries

How might the insights from this study on the role of Kdm6b in hippocampal NSC maintenance inform the development of therapeutic interventions for cognitive disorders associated with KDM6B mutations

The insights from this study on the role of Kdm6b in hippocampal NSC maintenance could potentially inform the development of therapeutic interventions for cognitive disorders associated with KDM6B mutations. Understanding the critical role that Kdm6b plays in the establishment and maintenance of NSCs in the mouse hippocampus provides a foundation for targeted interventions. By elucidating the specific molecular pathways and gene expression changes associated with Kdm6b deficiency, researchers can identify potential therapeutic targets for restoring NSC function in individuals with KDM6B mutations. For example, the identification of downstream genes involved in NSC maintenance that are dysregulated in Kdm6b-deleted NSCs could lead to the development of small molecule modulators or gene therapies to restore proper gene expression patterns and promote NSC survival and function. Additionally, the knowledge gained from this study could guide the development of personalized treatment strategies based on the specific molecular defects present in individuals with KDM6B mutations, ultimately leading to more effective therapeutic interventions for cognitive disorders.

What other chromatin regulators or transcriptional mechanisms might interact with Kdm6b to coordinately control the establishment and maintenance of the adult hippocampal NSC population

Several other chromatin regulators and transcriptional mechanisms may interact with Kdm6b to coordinately control the establishment and maintenance of the adult hippocampal NSC population. One potential player is EZH2, a Polycomb factor that catalyzes H3K27me3, the histone modification that KDM6B demethylates. EZH2 is known to be required for the proliferation of neural progenitor cells, and its interaction with KDM6B could regulate the balance of H3K27me3 levels at key regulatory elements involved in NSC maintenance. Additionally, chromatin remodelers such as CHD7 and BRG1, which have been implicated in adult DG neurogenesis, may also interact with Kdm6b to regulate gene expression programs essential for NSC function. Transcription factors like Notch signaling components and Id proteins, which are critical for NSC maintenance and differentiation, could also crosstalk with Kdm6b to coordinate the transition from stem cell state to neuronal fate in the hippocampus. By investigating the interplay between Kdm6b and these chromatin regulators and transcriptional mechanisms, researchers can gain a more comprehensive understanding of the complex regulatory network governing adult hippocampal neurogenesis.

Could the precocious differentiation of Kdm6b-deleted DG NSCs be leveraged to better understand the molecular signals that drive the transition from a stem cell state to a neuronal fate during hippocampal development

The precocious differentiation of Kdm6b-deleted DG NSCs could serve as a valuable model for studying the molecular signals that drive the transition from a stem cell state to a neuronal fate during hippocampal development. By analyzing the gene expression changes associated with the premature differentiation of NSCs in the absence of Kdm6b, researchers can identify key regulators and pathways involved in the neurogenic process. This information could shed light on the molecular mechanisms that normally maintain NSCs in a quiescent state and prevent premature differentiation. Additionally, studying the transition from NSCs to neuroblasts in the context of Kdm6b deficiency may reveal novel targets for modulating neurogenesis in therapeutic settings. By leveraging the insights gained from the precocious differentiation phenotype, researchers can uncover critical molecular signals and pathways that govern the balance between NSC maintenance and neuronal differentiation in the hippocampus, ultimately advancing our understanding of neurogenesis and potential therapeutic strategies for cognitive disorders.