Modeling neurodevelopmental disorders in vitro and mechanistic dissection using embryonic stem cells
Zhonghua Gao, PhD
Assistant Professor, Department of Biochemistry and Molecular Biology
Penn State Cancer Institute Cancer Institute, Next-Generation Therapies
Time: May 20, 2021 12:00 PM Eastern Time (US and Canada)
ZOOM: https://psu.zoom.us/j/96976467825?pwd=YlNtUVBGUzlibGY1eHNCYnZvbjZKdz09
Neurodevelopmental disorders (NDD) result from compromised development of the central nervous system and encompass but are not limited to Autism Spectrum Disorders (ASD), Developmental Delay (DD) and Intellectual Disabilities (ID). Recently, Autism Susceptibility Candidate 2 (AUTS2) has been identified as one of most frequently disrupted genes in NDD. Disruption of AUTS2 leads to common neurodevelopmental abnormalities including microcephaly, developmental delay, and varying degrees of intellectual disability. The importance of AUTS2 in neurodevelopment has been confirmed using animal models and embryonic stem cells (ESC). However, the mechanisms by which AUTS2 regulates neuronal fate at the molecular level remain unclear. Our previous studies have shown that nuclear AUTS2 comprises a type 1 Polycomb repressive complex (PRC1) and converts PRC1 from transcriptional repressors to activators. However, cytosolic AUTS2 seems to be crucial for neuronal migration and neuritogenesis in mouse cortex through the activation of Rac1. Additional factors that interact with AUTS2 also have been identified and likely play roles in neurodevelopment. Our lab employs embryonic stem cell derived models and multiple approaches to understand how AUTS2 disruption affect neuronal lineage specification. Our unpublished data suggests AUTS2 regulates the neuronal differentiation through engaging, in a stage specific manner, important signaling pathways. This study will likely provide new directions for the development of effective therapeutic interventions in NDD.
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