Early myeloid lineage specification mechanisms at the top of the hematopoietic hierarchy

Elucidating how lineage specification occurs at the top of the hematopoietic hierarchy has tremendous implications for treating impaired blood production. The critical contribution of lineage-biased multipotent progenitors (MPPs) to steady-state hematopoiesis emphasizes the importance of uncovering the mechanisms underlying lineage-biased MPP production from hematopoietic stem cells (HSCs) and the lineage specification mechanisms at the MPP population. Despite its potential clinical significance to efficiently modulate myeloid cell production, how initial myeloid lineage specification occurs at the adult HSCs and MPP populations remain poorly understood. Our recent discoveries of distinct subsets within a granulocyte/macrophage (G/M)-biased MPP, MPP3 and their differential lineage potentials indicate the bifurcation point for G/M versus erythroid lineage at the MPP3. Based on those findings, this proposal aims to establish signaling pathways that control G/M versus erythroid cell production at the HSC and MPP levels. In Aim 1, we will investigate the role of Notch2 signaling in the production of erythroid lineage cells using old mice and Notch2 gain-of-function mice. In Aim 2, we will interrogate the function of unfolded protein response (UPR) signaling in the production of myeloid cells in vivo using chemical activators and inhibitors. Collectively, these studies will verify the function of Notch2 and UPR signaling in the production of erythroid and myeloid cell production in vivo, respectively.