PhD student at the Institute of Neuroanatomy, Centre for Anatomy, University Medical Centre Goettingen (UMG) in the research group of Dr. Tran Tuoc (Director: Prof. Dr. Jochen Staiger)
‘’Development of a novel biosensor to detect glucocorticoid signalling and stress response in vivo in zebrafish larvae’’. Thesis advisor: Dr. Soojin Ryu, Developmental Genetics of the Nervous system, Max Planck Institute for Medical Research, Heidelberg, Germany
International Max Planck Research School (IMPRS) for Neurosciences, Georg-August University of Goettingen, Germany
Laboratory of Dr. Soumya Iyengar, Systems Neuroscience division, National Brain Research Centre, Manesar, India
Shanmugha Arts Science Technology & Research Academy (SASTRA) University, Thanjavur, India
In mammals, evolution of the neocortex is considered to have significantly contributed to higher cognitive functions. Mammalian cortex, a highly specialized six-layered structure, is further divided into distinct sensory, motor and association areas. Interestingly, the size and complexity of the cortex is achieved by neural progenitor cells of the ventricular (VZ) and subventricular zones (SVZ) early in development. In the background of recent evidences suggesting the role of mSWI/SNF (or BAF) complexes in cortical neurogenesis, I am interested to further investigate the role of BAF complex and its interaction partners in regulating cortical development in mouse.
BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knock-out (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and down-regulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3, UTX) and potentiate their activity. Importantly BAF complexes are indispensable for forebrain development, including proliferation, differentiation and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls global transcriptional program and chromatin state in development.
ATP-dependent BAF chromatin remodeling complexes play an essential role in the maintenance of the gene expression program by regulating the structure of chromatin. There is increasing evidence that BAF complexes based on the alternative ATPase subunits, Brg1 and Brm, control the differentiation of neural stem cells (NSCs) to generate distinct neural cell types and modulate trans-differentiation between cell types. The BAF complexes have dedicated functions at different stages of neural differentiation that appear to arise by combinatorial assembly of their subunits. Furthermore, the differentiation of NSCs is regulated by the tight interactions between the BAF chromatin remodeling complex and the transcriptional machinery. Here, we review recent insights into the functional interaction between BAF complexes and various transcription factors (TFs) in neural differentiation and cellular reprogramming
The multi-subunit chromatin remodeling BAF complex controls different developmental processes. Using cortex-specific conditional knockout and overexpression mouse models, we have recently reported that BAF170, a subunit of the vertebrate BAF chromatin remodeling complex, interacts with transcription factor (TF) Pax6 to control cortical size and volume. The mechanistic basis includes suppression of the expression of Pax6 target genes, which are required for genesis of cortical intermediate progenitors (IPs) and specification of late neuronal subtype identity. In addition, we showed that a dynamic competition between BAF170 and BAF155 subunits within the BAF complex during progression of neurogenesis is a primary event in modulating the size of the mammalian cortex. Here, we present additional insights into the interaction between the BAF complex and TF Pax6 in the genesis of IPs of the developing cortex. Furthermore, we show that such competition between BAF170 and BAF155 is involved as well in the determination of the size of the embryonic body. Our results add new insights into a cell-intrinsic mechanism, mediated by the chromatin remodeling BAF complex, that controls vertebrate body shape and size.