Smad2 and Smad3 coordinately regulate craniofacial and endodermal development.
Ligands of the transforming growth factor-beta (TGF-beta) superfamily are involved in numerous developmental and disease processes. TGF-beta, activins, and nodal ligands operate through the highly homologous Smad2 and Smad3 intracellular mediators. Smad2 mutants exhibit early embryonic lethality, while Smad3 mutants are viable, but show a plethora of postnatal phenotypes, including immune dysfunction and skeletal abnormalities. Previously, we have shown that the Smad2 and Smad3 genes function cooperatively during liver morphogenesis. Here we show that Smad2 and Smad3 are required at a full dosage for normal embryonic development. Animals lacking one allele of each gene exhibit a variably penetrant phenotype in which structures in the anterior and ventral midline are reduced or lost; additionally, we demonstrate that this craniofacial defect and the previously reported hepatic phenotypes are both due to defects in the definitive endoderm. A reduction of endodermal gene expression as well as a failure to displace the visceral endoderm occurs despite the formation of a normal foregut pocket. This precedes any defects in anterior patterning and likely causes the abnormalities observed in craniofacial and midline development, as well as hepatogenesis.
Liu
Ye
Y
Program in Molecular, Cellular, and Developmental Biology, Ohio State University, Columbus, OH 43210-1392, USA.
Festing
Maria
M
Thompson
John C
JC
Hester
Mark
M
Rankin
Scott
S
El-Hodiri
Heithem M
HM
Zorn
Aaron M
AM
Weinstein
Michael
M
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004707:Endoderm / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006652:Histological Techniques; D017403:In Situ Hybridization; D051379:Mice / Q000196:embryology*; D008817:Mice, Mutant Strains; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C497789:madh3 protein, Xenopus