Understanding the mechanisms that control self-renewal and differentiation of neural progenitor/stem cells

Neural progenitor/stem cells can self renew and are capable of generating neurons and glia, the major cell types that constitute the central nervous system. They are fundamentally important in the development of a functional nervous system. The multipotent potential and the ability to self-renew also make them promising candidates in cell-based replacement therapy for repairing damaged nerves or treating neurological disorders. Under physiological conditions, neural progenitor/stem cells maintain a balance between the two cell states -- self-renewal and differentiation, and can shift the balance in response to environmental cues. Loss of this homeostasis can lead to defects in brain development and may be the cause of brain cancers. The long-term goal of our laboratory is to understand the mechanisms that govern self-renewal and differentiation and to apply this knowledge to developing novel treatment for neural regeneration and brain cancers. We study neural progenitor/stem cells using combined molecular, cell biological and genetic approaches.

Our current research was directed towards identifying molecular determinants important for the self-renewal and differentiation of neural progenitor cells in the mammalian cerebral cortex. During development, neural progenitor cells of the cerebral cortex initially expand within the ventricular zone (VZ). As corticogenesis proceeds, they differentiate into neurons, which migrate out of the VZ into their final residence in the cortical plate (CP). This developmental progression of cortical neurogenesis provides a particularly good platform for studying neural progenitor cell self-renewal, differentiation, and migration.

Our on-going studies include two parallel approaches: (1) We have recently discovered that ephrin-B and heterotrimeric G protein signaling pathways coordinately regulate the balance between self-renewal and differentiation of neural progenitor cells in the developing mouse cerebral cortex. Thus, we are continuing to investigate the functions and the mechanisms of action of the ephrin/Eph family signaling molecules and G proteins in neural progenitor/stem cells. (2) We also want to more broadly identify molecules and mechanisms critical for neural progenitor/stem cell regulation, in particular the epigenetic control of neural rogenitor cell state. Our strategy is to use genetic modification to differentially label neural progenitor cells and their immediate neuronal progeny in the mouse cerebral cortex. This differential labeling strategy provides us a platform to achieve co-purification of endogenous neural progenitor cells and their progeny. We can then apply advanced global genetic and epigenetic analysis to identify candidate regulators and mechanisms with respect to the decision of neural progenitor cells to either self-renew or differentiate.