BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Chromatin Biology

Background:

• mSWI/SNF (BAF) complexes regulate human neural development and are implicated in neurodevelopmental disorders.
• BAF subunit exchange generates neuron-specific nBAF complexes during neural stem/progenitor cell differentiation.

Purpose of the Study:

• To investigate the role of BAF subunit exchange timing in neural development.
• To elucidate the mechanism by which BAF53a loss affects neurogenesis and cell cycle progression.

Main Methods:

• In vivo manipulation of BAF subunit exchange timing.
• Analysis of cell cycle progression, neurogenesis, and chromatin accessibility.
• Investigating rescue mechanisms for BAF53a loss.

Main Results:

• Early loss of the npBAF subunit BAF53a stalls neural stem/progenitor cell cycle and disrupts neurogenesis.
• BAF53a loss decreases chromatin accessibility at key neural transcription factor binding sites due to Polycomb accumulation.
• Premature BAF53b expression rescues the cell cycle block, but extrinsic proliferative cues fail to do so.

Conclusions:

• BAF53a is essential for timely cell cycle exit and differentiation of neural progenitors.
• Polycomb accumulation and subsequent gene repression underlie the BAF53a-dependent cell cycle block.
• BAF53b plays a critical role in overcoming proliferative signals and driving neural progenitor cell cycle exit.