Hes repressors are essential regulators of hematopoietic stem cell development downstream of notch signaling

TY - JOUR

T1 - Hes repressors are essential regulators of hematopoietic stem cell development downstream of notch signaling

AU - Guiu, Jordi

AU - Shimizu, Ritsuko

AU - D'Altri, Teresa

AU - Fraser, Stuart T.

AU - Hatakeyama, Jun

AU - Bresnick, Emery H.

AU - Kageyama, Ryoichiro

AU - Dzierzak, Elaine

AU - Yamamoto, Masayuki

AU - Espinosa, Lluis

AU - Bigas, Anna

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs.

AB - Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs.

UR - http://www.scopus.com/inward/record.url?scp=84874508773&partnerID=8YFLogxK

U2 - 10.1084/jem.20120993

DO - 10.1084/jem.20120993

M3 - Journal article

C2 - 23267012

AN - SCOPUS:84874508773

SN - 0022-1007

VL - 210

SP - 71

EP - 84

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 1

ER -