EGR1 (Early Growth Response 1) is a well-known transcription factor of the immediate early gene family. My lab recently discovered an unexpected and intriguing role for EGR1 in regulating the activity of blood- forming hematopoietic stem cells (HSC). In particular, our extensive Preliminary Data demonstrate that EGR1 normally functions both to limit HSC proliferation and to promote HSC retention in the BM niche. These findings are significant for several reasons. First, EGR1 represents one of only a few known regulators of HSC quiescence, which is critical in preserving HSC function. Moreover, EGR1 represents the first identified transcriptional regulator of HSC migration, suggesting that targeting this factor may provide novel avenues to inducing stem cell mobilization for clinical transplant. Finally, and most remarkably, the role of this single gene in determining both the proliferation and anatomical localization of HSC reveals a novel and potentially broadly acting mechanism for controlling stem cell number whereby stem cell division is molecularly coordinated with retention in the niche. Egr1-/- mice thus present an extraordinary opportunity for discovering new and important insights into the fundamental properties of HSC and their clinical applications. Through two focused and complementary Specific Aims, the work proposed in this application will (1) determine by functional analyses whether the stem cell regulatory factor Bmi1 represents a key target gene responsible for EGR1-mediated effects on HSC proliferation and localization, (2) identify and functionally validate additional, novel targets of EGR1 that regulate HSC activity, and (3) elucidate the cellular mechanism(s) underlying the spontaneous mobilization of LT-HSC in Egr1-/- mice. These studies thus take advantage of EGR1 and Egr1-/- mice as unique model system to answer long-standing questions about the molecular and cellular regulation of HSC function.
Egr1 represents the first known transcriptional regulator of both HSC migration and proliferation. Thus, identification of the Egr1-regulated pathways active in HSC will be vital for developing a mechanistic understanding of these processes and their role in stem cell function. These findings will have significant implications both for understanding the normal, homeostatic control of HSC activity in blood formation and for manipulating stem cell activity clinically to improve the efficiency of HSC mobilization for donor cell harvest and to speed hematopoietic engraftment following transplantation.
|Rao, Tata Nageswara; Gupta, Manoj K; Softic, Samir et al. (2018) Attenuation of PKC? enhances metabolic activity and promotes expansion of blood progenitors. EMBO J 37:|
|Wang, Leo D; Ficarro, Scott B; Hutchinson, John N et al. (2016) Phosphoproteomic profiling of mouse primary HSPCs reveals new regulators of HSPC mobilization. Blood 128:1465-74|
|Rao, Tata Nageswara; Marks-Bluth, Jonathan; Sullivan, Jessica et al. (2015) High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice. Stem Cell Res 14:307-22|
|Wang, L D; Rao, T N; Rowe, R G et al. (2015) The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy. Leukemia 29:1320-30|
|Kolodin, Dmitriy; van Panhuys, Nicolas; Li, Chaoran et al. (2015) Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21:543-57|
|Le, Xiuning; Pugach, Emily K; Hettmer, Simone et al. (2013) A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development 140:2354-64|
|Nabors, L Karina; Wang, Leo D; Wagers, Amy J et al. (2013) Overlapping roles for endothelial selectins in murine hematopoietic stem/progenitor cell homing to bone marrow. Exp Hematol 41:588-96|
|Gazit, Roi; Garrison, Brian S; Rao, Tata Nageswara et al. (2013) Transcriptome analysis identifies regulators of hematopoietic stem and progenitor cells. Stem Cell Reports 1:266-80|
|Liu, Jianing; Hettmer, Simone; Milsom, Michael D et al. (2012) Induction of histiocytic sarcoma in mouse skeletal muscle. PLoS One 7:e44044|
|Wang, Leo D; Wagers, Amy J (2011) Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat Rev Mol Cell Biol 12:643-55|
Showing the most recent 10 out of 11 publications