Modulation of Noncanonical TGF-β Signaling Prevents Cleft Palate in Tgfbr2 Mutant Mice

J Clin Invest. 2012 Mar;122(3):873-85. doi: 10.1172/JCI61498. Epub 2012 Feb 13.

Abstract

Patients with mutations in either TGF-β receptor type I (TGFBR1) or TGF-β receptor type II (TGFBR2), such as those with Loeys-Dietz syndrome, have craniofacial defects and signs of elevated TGF-β signaling. Similarly, mutations in TGF-β receptor gene family members cause craniofacial deformities, such as cleft palate, in mice. However, it is unknown whether TGF-β ligands are able to elicit signals in Tgfbr2 mutant mice. Here, we show that loss of Tgfbr2 in mouse cranial neural crest cells results in elevated expression of TGF-β2 and TGF-β receptor type III (TβRIII); activation of a TβRI/TβRIII-mediated, SMAD-independent, TRAF6/TAK1/p38 signaling pathway; and defective cell proliferation in the palatal mesenchyme. Strikingly, Tgfb2, Tgfbr1 (also known as Alk5), or Tak1 haploinsufficiency disrupted TβRI/TβRIII-mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice, indicating that activation of this noncanonical TGF-β signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice. Thus, modulation of TGF-β signaling may be beneficial for the prevention of congenital craniofacial birth defects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cleft Palate / genetics*
  • Crosses, Genetic
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence / methods
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Proteoglycans / genetics
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*

Substances

  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • betaglycan
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II