UC San Diego

It is now widely accepted that the fine balance between hematopoietic stem cell (HSC) self-renewal and differentiation is required for blood cell homeostasis and is evidently orchestrated by the dynamic interplay between environmental cues and intrinsic genetic setup. Nevertheless, how the niche signal-initiated intracellular signaling cascades are regulated in HSCs is less understood. The Stem cell factor (SCF)/Kit system has served as a classical model in deciphering molecular signaling events in the hematopoietic compartment. It has long been known that the microenvironment, or the so- called niche, of Sl/Sl mouse (steel-Dickie mice) that harbors a mutation in membrane-bound SCF or Kit-ligand, is not capable of supporting normal HSC functions. Study of various white spotting (W) mutant mice revealed an essential role of SCF-Kit signaling in HSC survival and quiescence maintenance. Kit is now a most frequently used marker for HSCs and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. In this dissertation, we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling loop. Inducible ablation of none-receptor protein tyrosine phosphatase number 11 (PTPN11/Shp2) in adult hematopoietic compartment led to severe cytopenia in bone marrow, spleen and peripheral blood in mice. Shp2 removal resulted in elevated HSC death and loss of HSC quiescence, causing suppression of the functional HSCs/progenitors pool. Shp2- deficient HSCs failed to reconstitute lethally irradiated recipients in a cell autonomous manner due to combined defects in homing, self-renewal and survival. We show that Shp2 regulates coordinately multiple signals, including AKT, MAPK and STAT3 pathways, to promote Kit expression via the transcriptional factor Gata2. Therefore, this study reveals a novel signaling mechanism of kinase- phosphatase-kinase cascade in HSCs/progenitors in adult mammals