The scaffolding molecule, Gab2, is a key regulator in neural stem cell biology and hematopoietic cell signaling.

摘要

Stem cells play important roles in the development and maintenance of many tissues in mammals. Neural stem cells (NSCs) have been isolated from two neurogenic zones in the adult brain, the subventricular zone (SVZ) and the hippocampal dentate gyrus. In the presence of basic Fibroblast Growth Factor (bFGF) or Epidermal Growth Factor (EGF), these cells self renew in vitro and exhibit multipotency.; How growth factors regulate stem cell self renewal and differentiation remains poorly understood. In my first project, I have addressed this question by examining the role of an important class of signaling molecules using in vitro stem cell models. The Gab family of docking proteins couples growth factor receptors to essential signaling pathways. Retinoic acid (RA) promotes pluripotent cells such as P19 and embryonic stem (ES) cells to adopt a neural fate. We found that Gab2 expression was significantly increased when P19 or ES cells were induced by RA to differentiate along the neural lineage. Moreover, Gab2 was expressed mainly in neurons, suggesting that Gab2 maybe involved in neuronal differentiation. Using RNA interference, Gab2 silencing impaired the ability of P19 cells to undergo neuronal differentiation. Next, we examined the role of Gab2 in NSCs. Compared to undifferentiated ES or P19 cells, Gab2 levels were much higher in NSCs. Using the neurosphere colony assay, Gab2 silencing significantly reduced the ability of NSCs to form bFGF-dependent neurospheres. Additionally, Gab2 silencing specifically increased neuronal but not glial apoptosis, leading to a significant reduction in neuron production. Our study provides new insights into how growth factors diversify their functions through adaptor proteins to regulate neurogenesis.; In my second project, I studied the role of Gab2 in myeloid cells. We found that Gab2 is required for optimal Colony Stimulating Factor-1 (CSF-1)-mediated cell proliferation, but not that dependent on interleukin-3. Gab2 knockdown reduced AKT but not ERK activation in response to CSF-1. Overexpression of Gab2 stimulates CSF-1-mediated proliferation, but this is not correlated with increased AKT activity. Our results suggest that Gab 2 is required for CSF-1-induced AKT activation, and regulates cell proliferation through both AKT-dependent and -independent pathways.