The role of EMT transcription factor Zeb2 in fetal hematopoiesis

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PROJECT SUMMARY Our goal is to understand the transcriptional requirements for erythroid-myeloid progenitor (EMP) development and differentiation into monocytes and tissue resident macrophages (TRM). Hematopoiesis is comprised of three waves: primitive hematopoiesis, transient-definitive hematopoiesis and definitive hematopoiesis1–6. Transient-definitive and definitive hematopoiesis require EMPs and hematopoietic stem cell (HSCs), respectively. EMPs are required for embryonic development until HSCs take over as the primary hematopoietic progenitors and thus absence of EMPs results in midgestation lethality7. Despite their importance in fetal development, much remains unknown regarding the transcriptional requirements for EMP development, in part due to shared surface markers and genetic programs between overlapping waves of hematopoiesis and terminally differentiated lineages. Additionally, EMP-derived monocytes are recognized as the main source of majority of the TRM populations in adults4,8,9. TRMs are eventually replaced in the adult by HSC-derived monocytes at tissue-specific rates. The developmental and functional differences between EMP- derived and HSC-derived TRM and the impact on tissue homeostasis are not well-understood. Previous studies and preliminary data indicate that the transcriptional factor Zeb2 is not only required for the maintenance of TRM identity but also required for EMP formation and/or differentiation. We hypothesize that Zeb2 is required for the development and differentiation of primitive hematopoietic progenitors and transient- definitive EMPs. We aim to identify novel regulatory elements and transcription factors regulating Zeb2 expression during primitive and transient-definitive hematopoiesis. I am currently a MD-PhD candidate at Washington University in St. Louis School of Medicine, an institution with a long history of supporting physician-scientists at all stages of their training and is working with a strongly committed mentoring team. The proposed training plan provides new conceptual and technical training, along with scientific, clinical, and career development activities that support a trajectory to become an independent physician-scientist focused on discovering mechanisms of hematopoietic development and lineage differentiation and applying this knowledge toward advancing novel therapeutic strategies.