Dataset Information

Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.

ABSTRACT: 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.

SUBMITTER: Dudas M

PROVIDER: S-EPMC1557652 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.

Dudas Marek M Kim Jieun J Li Wai-Yee WY Nagy Andre A Larsson Jonas J Karlsson Stefan S Chai Yang Y Kaartinen Vesa V

Developmental biology 20060527 2

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 pa ...[more]

PMID: 16806156

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Project description:Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus.To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays.Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools.We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion.Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.The previous version was incorrect. New authors Ali Nawshad, Hasan Otu, Janki Sharma, and Elizabeth Sheldon have been included in this version; the funding and acknowledgement sections have been updated accordingly; the article title, some text, and one supplementary data file have been edited; and the corresponding author has been changed. The original corresponding author regrets these earlier errors.

Dataset Information

Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.

Publications

Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.

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