Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice.
Deletion of the transforming growth factor beta1 (TGF-beta1) gene in mice has previously suggested that it regulates both hematopoiesis and angiogenesis. To define the function of TGF-beta more precisely, we inactivated the TGF-beta type I receptor (TbetaRI) gene by gene targeting. Mice lacking TbetaRI die at midgestation, exhibiting severe defects in vascular development of the yolk sac and placenta, and an absence of circulating red blood cells. However, despite obvious anemia in the TbetaRI(-/-) yolk sacs, clonogenic assays on yolk sac-derived hematopoietic precursors in vitro revealed that TbetaRI(-/-) mice exhibit normal hematopoietic potential compared with wild-type and heterozygous siblings. Endothelial cells derived from TbetaRI-deficient embryos show enhanced cell proliferation, improper migratory behavior and impaired fibronectin production in vitro, defects that are associated with the vascular defects seen in vivo. We thus demonstrate here that, while TbetaRI is crucial for the function of TGF-beta during vascular development and can not be compensated for by the activin receptor-like kinase-1 (ALK-1), functional hematopoiesis and development of hematopoietic progenitors is not dependent on TGF-beta signaling via TbetaRI.
Larsson
J
J
Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine and Department of Medicine, Lund University Hospital, Lund, Sweden.
Goumans
M J
MJ
Sjöstrand
L J
LJ
van Rooijen
M A
MA
Ward
D
D
Levéen
P
P
Xu
X
X
ten Dijke
P
P
Mummery
C L
CL
Karlsson
S
S
D030201:Activin Receptors, Type I; D000818:Animals; D002455:Cell Division; D002465:Cell Movement / Q000502:physiology; D005314:Embryonic and Fetal Development; D004730:Endothelium, Vascular / Q000166:cytology; D015672:Erythroid Precursor Cells; D005353:Fibronectins / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells; D016212:Transforming Growth Factor beta / Q000378:metabolism
D005353:Fibronectins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I