Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium

Il Ho Jang; Yi Fen Lu; Long Zhao; Pamela L. Wenzel; Tsutomu Kume; Sumon M. Datta; Natasha Arora; Jordi Guiu; Mounia Lagha; Peter G. Kim; Eun Kyoung Do; Jae Ho Kim; Thorsten M. Schlaeger; Leonard I. Zon; Anna Bigas; Caroline E. Burns; George Q. Daley

doi:10.1182/blood-2014-04-568170

Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium

Il Ho Jang, Yi Fen Lu, Long Zhao, Pamela L. Wenzel, Tsutomu Kume, Sumon M. Datta, Natasha Arora, Jordi Guiu, Mounia Lagha, Peter G. Kim, Eun Kyoung Do, Jae Ho Kim, Thorsten M. Schlaeger, Leonard I. Zon, Anna Bigas, Caroline E. Burns^*, George Q. Daley

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin⁺ hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.

Original language	English (US)
Pages (from-to)	1418-1426
Number of pages	9
Journal	Blood
Volume	125
Issue number	9
DOIs	https://doi.org/10.1182/blood-2014-04-568170
State	Published - 2015

Funding

This work was supported by grants from the Boston Children’s Hospital (PLE1009-0111 and SAF2010-15450); the National Institutes of Health, National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium (grant UO1-HL100001); the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (grant R24DK092760); and the Doris Duke Medical Foundation. G.Q.D. is an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. The authors thank Dr Jonghwan Kim (Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School for guiding us in analyzing microarray data, Elizabeth Paik and Michelle Lin (Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School) for sharing their zebrafish and experimental protocols, and Tom Gridley (Jackson Labs, Bar Harbor, ME) for providing the Jagged1 mutant mice. This work was supported by grants from the Boston Children's Hospital (PLE1009-0111 and SAF2010-15450); the National Institutes of Health, National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium (grant UO1-HL100001); the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (grant R24DK092760); and the Doris Duke Medical Foundation. G.Q.D. is an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research.

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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Jang, I. H., Lu, Y. F., Zhao, L., Wenzel, P. L., Kume, T., Datta, S. M., Arora, N., Guiu, J., Lagha, M., Kim, P. G., Do, E. K., Kim, J. H., Schlaeger, T. M., Zon, L. I., Bigas, A., Burns, C. E., & Daley, G. Q. (2015). Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood, 125(9), 1418-1426. https://doi.org/10.1182/blood-2014-04-568170

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title = "Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium",

abstract = "Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin+ hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.",

author = "Jang, {Il Ho} and Lu, {Yi Fen} and Long Zhao and Wenzel, {Pamela L.} and Tsutomu Kume and Datta, {Sumon M.} and Natasha Arora and Jordi Guiu and Mounia Lagha and Kim, {Peter G.} and Do, {Eun Kyoung} and Kim, {Jae Ho} and Schlaeger, {Thorsten M.} and Zon, {Leonard I.} and Anna Bigas and Burns, {Caroline E.} and Daley, {George Q.}",

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year = "2015",

doi = "10.1182/blood-2014-04-568170",

language = "English (US)",

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AU - Jang, Il Ho

AU - Lu, Yi Fen

AU - Zhao, Long

AU - Wenzel, Pamela L.

AU - Kume, Tsutomu

AU - Datta, Sumon M.

AU - Arora, Natasha

AU - Guiu, Jordi

AU - Lagha, Mounia

AU - Kim, Peter G.

AU - Do, Eun Kyoung

AU - Kim, Jae Ho

AU - Schlaeger, Thorsten M.

AU - Zon, Leonard I.

AU - Bigas, Anna

AU - Burns, Caroline E.

AU - Daley, George Q.

PY - 2015

Y1 - 2015

N2 - Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage-tracing studies have established that definitive hematopoietic stem and progenitor cells arise from vascular endothelial-cadherin+ hemogenic endothelial cells of the aorta-gonad-mesonephros region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and we identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis.

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Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium

Abstract

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ASJC Scopus subject areas

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