Chromatin remodeling BAF complex dependent mechanisms in development of cortical interneurons

by Xiaoyi Mao
Cumulative thesis
Date of Examination:2024-11-13
Date of issue:2025-10-21
Advisor:Prof. Dr. Jochen Staiger
Referee:Prof. Dr. Jochen Staiger
Referee:Prof. Dr. Nils Brose
Referee:Prof. Dr. Thomas Dresbach
Referee:Prof. Dr. André Fiala
Referee:Dr. Michael Heide
Referee:Prof. Dr. André Fischer
Persistent Address: http://dx.doi.org/10.53846/goediss-11540

 

 

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Abstract

English

GABAergic inhibitory neurons contribute to the excitatory and inhibitory balance in the brain. Dysfunction in GABAergic neuron development is implicated in various neurodevelopmental disorders. In recent years, the ATP-dependent BRG1/BRM-associated factor (BAF) chromatin remodeling complex has gained recognition for its essential role in neural development. While our prior research demonstrated that BAF complex scaffolding subunits BAF155 and BAF170 are vital for neurogenesis in the dorsal forebrain and oligodendrogenesis, the specific impact of BAF complex on GABAergic neuron development remains underexplored. Here, we report that both BAF155 and BAF170 were expressed in medial ganglionic eminence (MGE)-derived GABAergic lineages. Conditional deletion of these subunits in the MGE progenitors led to expanded progenitor pool and abnormal regional patterning in the ventricular zone (VZ). Moreover, the generation of MGE-specific neurons was severely reduced due to apoptosis and impaired proliferation and differentiation capacity of cells in the subventricular zone (SVZ). Some MGE precursors took on a lateral ganglionic eminence (LGE) character. In vitro, we also observed defects in neurite growth. GABAergic neuron migration was severely disrupted, causing a substantial number of cells to accumulate in the periventricular region of the subpallium, unable to reach the cortex, striatum, or globus pallidus (GP). Mechanistically, BAF complex affects NKX2.1 expression level and interacts with NKX2.1 to activate genes essential for neuron differentiation. Overall, our findings highlight the critical importance of BAF complex in regulating multiple aspects of GABAergic neuron development.
Keywords: BAF complex; Medial ganglionic eminence; Cortical interneurons; GABAergic neuron development; progenitors; NKX2.1
 
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