BMP and Wnt specify hematopoietic fate by activation of the Cdx-Hox pathway.
The formation of blood in the embryo is dependent on bone morphogenetic protein (BMP), but how BMP signaling intersects with other regulators of hematopoietic development is unclear. Using embryonic stem (ES) cells, we show that BMP4 first induces ventral-posterior (V-P) mesoderm and subsequently directs mesodermal cells toward blood fate by activating Wnt3a and upregulating Cdx and Hox genes. When BMP signaling is blocked during this latter phase, enforced expression of either Cdx1 or Cdx4 rescues hematopoietic development, thereby placing BMP4 signaling upstream of the Cdx-Hox pathway. Wnt signaling cooperates in BMP-induced hemogenesis, and the Wnt effector LEF1 mediates BMP4 activation of Cdx genes. Our data suggest that BMP signaling plays two distinct and sequential roles during blood formation, initially as an inducer of mesoderm, and later to specify blood via activation of Wnt signaling and the Cdx-Hox pathway.
Lengerke
Claudia
C
Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, MA 02115, USA.
Schmitt
Sabine
S
Bowman
Teresa V
TV
Jang
Il Ho
IH
Maouche-Chretien
Leila
L
McKinney-Freeman
Shannon
S
Davidson
Alan J
AJ
Hammerschmidt
Matthias
M
Rentzsch
Fabian
F
Green
Jeremy B A
JB
Zon
Leonard I
LI
Daley
George Q
GQ
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006413:Hematopoietic System / Q000196:embryology / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008648:Mesoderm / Q000196:embryology / Q000502:physiology; D051379:Mice; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000502:physiology
D019485:Bone Morphogenetic Proteins; C491272:Cdx1 protein, mouse; C084563:Cdx4 protein, mouse; D018398:Homeodomain Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins