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Histone-Binding Protein RBBP4 Is Necessary to Promote Neurogenesis in the Developing Mouse Neocortical Progenitors.

Sreeja Kumari Dhanya1, Kishan Kalia1, Sattwik Mohanty1

  • 1Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore 560065, India.

Eneuro
|November 26, 2024
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Summary

Chromatin modifier RBBP4 is essential for neocortical progenitor proliferation and deep-layer neurogenesis. It regulates neuron output by binding to distal elements, including the Cdon gene, impacting neurodevelopmental disorders.

Keywords:
CdonPolycomb repressive complexRbbp4histone-bindingmouse neocortical developmentneurogenesisnucleosome remodeling complex

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Chromatin regulation is vital for neocortical neurogenesis.
  • Mutations in chromatin modifiers are linked to neurodevelopmental disorders.
  • The role of RBBP4 in neocortical development is largely unknown.

Purpose of the Study:

  • To investigate the function and genome-wide occupancy of RBBP4 in neocortical progenitors.
  • To determine RBBP4's role in deep-layer neurogenesis and progenitor proliferation.
  • To identify potential RBBP4 target genes involved in neurogenesis.

Main Methods:

  • RBBP4 knockdown using CRISPR/Cas9 in mouse neocortical progenitors.
  • Analysis of neuronal output and progenitor proliferation.
  • Genome-wide occupancy analysis (ChIP-seq) to identify RBBP4 binding sites.
  • Gene knockdown and overexpression experiments for Cdon.

Main Results:

  • RBBP4 downregulation reduced neuronal output, particularly CTIP2-expressing neurons.
  • RBBP4 is essential for neocortical progenitor proliferation.
  • RBBP4 primarily binds to distal regulatory elements, with neuron differentiation as a key associated pathway.
  • RBBP4 binds to Cdon, a Shh pathway receptor; Cdon knockdown phenocopies RBBP4 knockdown effects.
  • CDON overexpression rescues RBBP4 loss-induced neurogenesis defects.

Conclusions:

  • RBBP4 is a critical regulator of neocortical progenitor proliferation and deep-layer neurogenesis.
  • RBBP4 controls neurogenesis through binding to distal regulatory elements, including the Cdon gene.
  • CDON is identified as a novel regulator of deep-layer neurogenesis, functionally linked to RBBP4.
  • These findings provide insights into chromatin regulation's role in neurodevelopment and neurodevelopmental disorders.