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

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