Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition

Peter Geon Kim, Colleen E. Albacker, Yi Fen Lu, Il Ho Jang, Yoowon Lim, Garrett C. Heffner, Natasha Arora, Teresa V. Bowman, Michelle I. Lin, M. William Lensch, Alejandro De Los Angeles, Leonard I. Zon, Sabine Loewer, George Q. Daley

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

During development, the hematopoietic lineage transits through hemogenic endothelium, but the signaling pathways effecting this transition are incompletely characterized. Although the Hedgehog (Hh) pathway is hypothesized to play a role in patterning blood formation, early embryonic lethality of mice lacking Hh signaling precludes such analysis. To determine a role for Hh signaling in patterning of hemogenic endothelium, we assessed the effect of altered Hh signaling in differentiating mouse ES cells, cultured mouse embryos, and developing zebrafish embryos. In differentiating mouse ES cells andmouse yolk sac cultures, addition of Indian Hh ligand increased hematopoietic progenitors, whereas chemical inhibition of Hh signaling reduced hematopoietic progenitors without affecting primitive streak mesoderm formation. In the setting of Hh inhibition, induction of either Notch signaling or overexpression of Stem cell leukemia (Scl)/T-cell acute lymphocytic leukemia protein 1 rescued hemogenic vascular-endothelial cadherin+ cells and hematopoietic progenitor formation. Together, our results reveal that Scl overexpression is sufficient to rescue the developmental defects caused by blocking the Hh and Notch pathways, and inform our understanding of the embryonic endothelial-to-hematopoietic transition.

Original languageEnglish (US)
Pages (from-to)E141-E150
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number2
DOIs
StatePublished - Jan 8 2013
Externally publishedYes

Keywords

  • AGM
  • Dorsal aorta
  • Hematopoietic stem cell
  • Runx1
  • Tie2

ASJC Scopus subject areas

  • General

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  • Cite this

    Kim, P. G., Albacker, C. E., Lu, Y. F., Jang, I. H., Lim, Y., Heffner, G. C., Arora, N., Bowman, T. V., Lin, M. I., Lensch, M. W., De Los Angeles, A., Zon, L. I., Loewer, S., & Daley, G. Q. (2013). Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. Proceedings of the National Academy of Sciences of the United States of America, 110(2), E141-E150. https://doi.org/10.1073/pnas.1214361110