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Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development
Matías Alvarez-Saavedra1,2,3, Keqin Yan1, Yves De Repentigny1
1Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Frontiers in Molecular Neuroscience
|November 5, 2019
Summary
Inactivating the Smarca5 gene impairs embryonic intermediate progenitor cells, leading to reduced upper layer neurons and corpus callosum agenesis in adult mice. This highlights Snf2h
Area of Science:
- Neuroscience
- Developmental Biology
- Epigenetics
Background:
- Cortical progenitor cell homeostasis is crucial for brain development; disruptions lead to microcephaly and cognitive deficits.
- Epigenetic regulators, including ISWI chromatin remodelers, play key roles in progenitor cell proliferation and neuron production.
- Previous studies showed Snf2l (Smarca1) inactivation causes macrocephaly due to Foxg1 dysregulation and IPC proliferation issues.
Purpose of the Study:
- To investigate the role of the Smarca5 gene, encoding the Snf2h chromatin remodeler, in embryonic cortical development.
- To determine the consequences of Smarca5 inactivation on intermediate progenitor cells (IPCs) and neuronal specification.
Main Methods:
- Generation of telencephalon-specific Smarca5 conditional knockout (cKO) mouse embryos.
- Analysis of embryonic brain development, including cell cycle kinetics, cell death, and progenitor cell populations (Tbr2+, FoxG1+).
- Assessment of adult mouse brain structure (corpus callosum agenesis) and neuronal populations (Satb2+), as well as molecular changes (clustered protocadherens) and behavior.
Main Results:
- Smarca5 inactivation in telencephalon-specific cKO embryos resulted in impaired cell cycle kinetics and increased cell death.
- A significant reduction in Tbr2+ and FoxG1+ intermediate progenitor cells (IPCs) was observed by mid-neurogenesis.
- Adult mice exhibited a marked decrease in Satb2+ upper layer neurons and partial agenesis of the corpus callosum.
- Reduced expression of clustered protocadherin genes was noted, potentially impacting dendritic arborization and leading to hyperactivity.
Conclusions:
- The Snf2h chromatin remodeler, encoded by Smarca5, is essential for embryonic intermediate progenitor cell expansion and the development of callosal projection neurons.
- Loss of Snf2h function during development leads to specific deficits in upper layer cortical neurons and white matter structure.
- These findings reveal a critical role for Snf2h-dependent chromatin remodeling in the precise regulation of mammalian brain development.
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