Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.
Transforming growth factor beta (TGF-beta) proteins play important roles in morphogenesis of many craniofacial tissues; however, detailed biological mechanisms of TGF-beta action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-beta type II receptor (TGFbetaRII), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and Alk5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-beta, and (2) ALK5 acts also in conjunction with type II receptors other than TGFbetaRII.
Dudas
Marek
M
Developmental Biology Program, The Saban Research Institute of Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Kim
Jieun
J
Li
Wai-Yee
WY
Nagy
Andre
A
Larsson
Jonas
J
Karlsson
Stefan
S
Chai
Yang
Y
Kaartinen
Vesa
V
D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004475:Ectoderm / Q000502:physiology*; D004848:Epithelium / Q000002:abnormalities / Q000196:embryology; D005145:Face / Q000002:abnormalities / Q000196:embryology*; D006801:Humans; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009432:Neural Crest / Q000002:abnormalities / Q000166:cytology / Q000502:physiology; D010159:Palate / Q000002:abnormalities / Q000196:embryology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D020033:Protein Isoforms; 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; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat