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 language | English (US) |
|---|---|
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 110 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 8 2013 |
| Externally published | Yes |
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Keywords
- AGM
- Dorsal aorta
- Hematopoietic stem cell
- Runx1
- Tie2
ASJC Scopus subject areas
- General
Cite this
Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. / Kim, Peter Geon; Albacker, Colleen E.; Lu, Yi Fen; Jang, Il Ho; Lim, Yoowon; Heffner, Garrett C.; Arora, Natasha; Bowman, Teresa V.; Lin, Michelle I.; Lensch, M. William; De Los Angeles, Alejandro; Zon, Leonard I.; Loewer, Sabine; Daley, George Q.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 2, 08.01.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition
AU - Kim, Peter Geon
AU - Albacker, Colleen E.
AU - Lu, Yi Fen
AU - Jang, Il Ho
AU - Lim, Yoowon
AU - Heffner, Garrett C.
AU - Arora, Natasha
AU - Bowman, Teresa V.
AU - Lin, Michelle I.
AU - Lensch, M. William
AU - De Los Angeles, Alejandro
AU - Zon, Leonard I.
AU - Loewer, Sabine
AU - Daley, George Q.
PY - 2013/1/8
Y1 - 2013/1/8
N2 - 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.
AB - 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.
KW - AGM
KW - Dorsal aorta
KW - Hematopoietic stem cell
KW - Runx1
KW - Tie2
UR - http://www.scopus.com/inward/record.url?scp=84872190285&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872190285&partnerID=8YFLogxK
U2 - 10.1073/pnas.1214361110
DO - 10.1073/pnas.1214361110
M3 - Article
C2 - 23236128
AN - SCOPUS:84872190285
VL - 110
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 2
ER -