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Regulation of neural stem cell proliferation during development and adulthood
Basic, autonomous and higher, voluntary cognitive functions of the brain require production of an immense diversity of neuron types at the right place and time, as well as correct wiring of these neurons into an array of functional neuronal circuits. Cell division of undifferentiated neural stem cells (NSCs) and committed neural progenitors drives neuron production. It is well accepted that abnormal NSC and progenitor division patterns in space and time are associated with neurodevelopmental disorders, including microcephaly and autism, as well as neurodegenerative disease and cancer. Stem cell therapies are gaining traction as potential treatment options, but uncontrolled, rampant stem cell division or production of the wrong neuron types pose risks with serious consequences. There have been tremendous advances in our understanding of NSC proliferation regulation from in vitro and in vivo studies of the brain, and more recently from organoid cultures, but our understanding of how NSC proliferation decisions are coordinated within the context of whole animal physiology during development and in adulthood is still rudimentary. In particular, it remains unclear how NSC intrinsic programs integrate with NSC extrinsic factors, local and systemic, to control number and type of neurons produced in time and space. To better understand NSC regulation in intact brains in whole organisms during development and aging, under normal versus diseased states, and in response to changing natural environments, the use of multi-disciplinary approaches and appropriate model systems is paramount. Research in the Siegrist lab is focused on the following fundamental themes and questions: 1. Nutrient-dependent control of NSCs in their niche. 2. Intrinsic genetic programs and temporal identity factors that control NSC proliferation timing and neuronal diversity. 3. Neural circuits involved in nutrient sensing and brain growth control. 4. Evolution and adaptation of NSC temporal patterning with developmental timing.