Abstract
Neural stem cells (NSCs) and neural progenitor cells (NPCs) are distinct groups of cells present in the embryonic and adult mammalian central nervous system (CNS). Proliferation of NSCs and NPCs is regulated by several molecular factors including the cyclin dependant kinase inhibitors (CDKI), such as p16Ink4a, and negative regulators of cell cycle, such as p19Arf. Chromatin proteins, including chromatin protein high mobility group A2 (HMGA2), regulate the expression of p16Ink4a and p19Arf in NSCs and NPCs, demonstrating the critical regulatory role that chromatin proteins play in NSC and NPC proliferation. In addition to HMGA2, it is likely that other chromatin proteins expressed in NSCs can and mediate NSC proliferation. The purpose of this project was to: 1) study and characterize the expression of HMG-B family members in NSCs, 2) test the hypothesis that HMGB2 regulates proper maintenance of adult subventricular zone (SVZ) NSCs and NPCs, and 3) test the hypothesis that changes in HMGB2-dependant progenitor maintenance in vivo is mechanistically related to changes in expression of different CDKIs in adult SVZ progenitor cells. Using neurosphere assays, I have determined the differential expression of HMGB mRNAs in proliferating and differentiating NSCs. HMG-B chromatin proteins, and predominantly HMGB2, were dynamically expressed in NSCs suggesting a possible regulatory role in NSC proliferation and neurogenesis. I performed in vivo proliferation and differentiation assays using HMGB2-/- mice to determine the role of HMGB2 in SVZ NSC proliferation and olfactory bulb (OB) neurogenesis. Young adult HMGB2-/- mice had altered SVZ proliferation, and different numbers of SVZ neural progenitor cells. These cellular changes in the SVZ were associated with changes in expression in several cyclin dependant kinase inhibitors. Young adult HMGB2-/- mice displayed aberrant changes in the rates of newly born neurons in the olfactory bulb, demonstrating that HMGB2 is a mediator of proper proliferation of SVZ neural progenitor cells and OB neurogenesis.
