Grant: Project Grant

During mammalian development, stem cells must balance proliferation and differentiation to produce specialized cell types required to form different organs and tissues in the body. Understanding how stem cell fate decisions are regulated under normal conditions and how they are disrupted in pathogenic states are fundamental questions in developmental and cell biology. This knowledge also provides the foundation for understanding and potentially treating human developmental diseases. Upon differentiation, stem cells need to make substantial changes in their subcellular organelles and macromolecules. These changes are often facilitated by autophagy, a conserved "self-eating" process by which cytoplasmic contents are engulfed for degradation and recycling. Therefore, impairment in autophagy has been linked to stem cell defects and implicated in human developmental diseases. However, what controls the dynamic activation of autophagy to dictate timely and precise fate decisions of stem cells and how their dysregulation cause specific human diseases remain poorly understood. In this project, we aim to address these questions, building on the insights we recently gained from a group of patients with a novel rare neurodevelopmental disorder caused by de novo genetic mutations affecting an enzyme regulating protein stability. We plan to use genetically modified mouse models to investigate how this enzyme controls autophagy activation for stem cell fate decisions during brain development, and dissect the pathogenic mechanisms by which the genetic mutations cause the clinical symptoms in our patient cohort.