Modulation of noncanonical TGF-? signaling prevents cleft palate in Tgfbr2 mutant mice.

ABSTRACT: Patients with mutations in either TGF-? receptor type I (TGFBR1) or TGF-? receptor type II (TGFBR2), such as those with Loeys-Dietz syndrome, have craniofacial defects and signs of elevated TGF-? signaling. Similarly, mutations in TGF-? receptor gene family members cause craniofacial deformities, such as cleft palate, in mice. However, it is unknown whether TGF-? 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-?2 and TGF-? receptor type III (T?RIII); activation of a T?RI/T?RIII-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 T?RI/T?RIII-mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice, indicating that activation of this noncanonical TGF-? signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice. Thus, modulation of TGF-? signaling may be beneficial for the prevention of congenital craniofacial birth defects.

SUBMITTER: Iwata J 

PROVIDER: S-EPMC3287237 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature