Role of chromatin remodelling BAF complex in fate regulation of ventral neural stem cells in the developing telencephalon
by Eman Ahmed Ahmed Mohamed Abbas
Date of Examination:2020-09-16
Date of issue:2021-01-14
Advisor:Prof. Dr. Jochen F. Staiger
Referee:Prof. Dr. André Fiala
Referee:Prof. Dr. Rüdiger Behr
Referee:Prof. Dr. Nils Brose
Referee:Prof. Dr. Jörg Wilting
Referee:PD Dr. Jürgen Becker
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EnglishA role for the multi-subunit BAF (mammalian SWI/SNF) complex in brain development has been postulated as its dysfunction causes several neurological diseases, including intellectual disability, schizophrenia, autism spectrum disorders, and amyotrophic lateral sclerosis. Despite this disease-related interest, there is little known about regulatory mechanisms exerted by BAF complex in the proliferative control of the oligodendrocytes (OL) progenitors, differentiation and migration of the GE-derived neuronal progenitors. Herein, we show that BAF complex acts as cell cycle regulator, controlling the dynamic balance between proliferation and differentiation of OL progenitors. OL progenitors are originated from three waves of the ventral and dorsal forebrain. Initially, Nkx2.1 expressing progenitors in the medial ganglionic eminence (MGE) specify into the first wave of oligodendrocyte precursor cells (OPCs) and then they migrate towards the cerebral cortex by E15.5. The second wave of OPCs is produced from the GSX2 expressing progenitors in the lateral and caudal ganglionic eminences (LGE and CGE) and arrives in the pallium at E16.5. Eventually, the third wave of the OPCs is generated after birth from Emx1- expressing cortical progenitors. Committed OPCs divide either symmetrically to produce a pair of cycling OPCs or asymmetrically to give rise to one proliferated OPC and one differentiated OL. Our findings pointed out that conditional loss of BAF complex caused a depleted pool of OL cells in the pallium and subpallium. Remarkably, the deletion of BAF complex impaired the proliferative capacity of the OPCs, and consequently diminished the ability of OLs differentiation and maturation. GE progenitors concurrently produce diverse neuronal and glial cell types. We focused on MGE progenitors since they share an initial developmental birthplace of the most GABAergic interneurons (INs) and the first wave of OPCs. The potential fate of the MGE progenitors is mainly controlled by the master transcription factors Dlx1 and Dlx2, which activate the development of the IN lineage and simultaneously, inhibit the progression of the OL lineage. Furthermore, we demonstrate that BAF complex has a pivotal role in commanding the MGE neurogenesis. Our data revealed that conditional absence of BAF complex in the MGE progenitors lead to severe lessening of the MGE-derived INs, along with impairment of neuronal differentiation and migration. Overall, these findings emphasize that BAF complex is crucial for proper proliferative division and enhance of OPCs and IN differentiation during murine brain development.
Keywords: Chromatin remodelling; BAF complex; Brain development; Developing telencephalon; Oligodendrocyte; Interneuron