# MEKK3 signaling in hemogenic endothelium

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $760,835

## Abstract

Project Summary
Embryonic definitive hematopoiesis is initiated by endothelial-hematopoietic transition
(EHT) in which endothelial cells alter fate to become hematopoietic progenitors and stem
cells. In mammals there are two major sites of EHT, the yolk sac vasculature and the
major arteries of the embryo (dorsal aorta, vitelline, umbilical). Although the process of
EHT is highly conserved and required for definitive hematopoiesis in all vertebrates, the
signals that control the conversion of vascular endothelial cells to hemogenic endothelial
cells are poorly understood. Recent studies have implicated hemodynamic shear forces
and inflammatory cytokines in promoting EHT, but how these diverse signals stimulate
the formation of hemogenic endothelium remains unknown. We have previously
demonstrated that the MEKK3 MAPK pathway mediates endothelial cell responses to
both inflammatory cytokines and hemodynamic shear forces, in large part by increasing
expression of the KLF2 and KLF4 transcription factors. Our preliminary studies
demonstrate that endothelial loss of MEKK3 or KLF2+KLF4 results in lethal fetal anemia
and failure of EHT in both the yolk sac and embryo. This proposal will test the
hypothesis that MEKK3-KLF2/4 signaling integrates endothelial cell stimulation by
cytokines and fluid forces to trigger EHT and the onset of definitive hematopoiesis.
These studies are expected to yield new insight into the signals that initiate EHT,
findings that may be used to generate new hematopoietic stem and progenitor cells for
therapeutic purposes later in life.

## Key facts

- **NIH application ID:** 9957193
- **Project number:** 5R01HL142976-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARK L KAHN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $760,835
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957193

## Citation

> US National Institutes of Health, RePORTER application 9957193, MEKK3 signaling in hemogenic endothelium (5R01HL142976-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9957193. Licensed CC0.

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