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Updated: May 10, 2026
Live Imaging of Mouse Secondary Palate Fusion
Published on: July 27, 2017
Modulation of noncanonical TGF-β signaling prevents cleft palate in Tgfbr2 mutant mice
Jun-ichi Iwata1, Joseph G Hacia, Akiko Suzuki
1Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California 90033, USA.
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.
Insights
Mutations in TGF-β receptors cause craniofacial defects. A noncanonical TGF-β pathway involving TβRI/TβRIII was identified as the cause, and its modulation may prevent birth defects.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Mutations in Transforming Growth Factor-beta (TGF-β) receptors, including TGF-β receptor type I (TGFBR1) and TGF-β receptor type II (TGFBR2), are linked to craniofacial defects and increased TGF-β signaling in humans (e.g., Loeys-Dietz syndrome).
- TGF-β receptor gene mutations also induce craniofacial deformities, such as cleft palate, in mouse models.
- The ability of TGF-β ligands to signal in Tgfbr2 mutant mice remained uninvestigated.
Purpose of the Study:
- To investigate the signaling mechanisms downstream of TGF-β receptors in mouse cranial neural crest cells.
- To determine the role of TGF-β ligands and specific signaling pathways in craniofacial malformations observed in Tgfbr2 mutant mice.
- To explore potential therapeutic targets for congenital craniofacial birth defects.
Main Methods:
- Analysis of gene expression, specifically TGF-β2 and TGF-β receptor type III (TβRIII), in mouse cranial neural crest cells lacking Tgfbr2.
- Investigation of signaling pathways, including SMAD-independent pathways like TRAF6/TAK1/p38, in the palatal mesenchyme.
- Assessment of cell proliferation defects in the palatal mesenchyme.
- Evaluation of craniofacial deformities in Tgfbr2 mutant mice with targeted haploinsufficiency of Tgfb2, Tgfbr1, or Tak1.
Main Results:
- Loss of Tgfbr2 in mouse cranial neural crest cells led to increased TGF-β2 and TβRIII expression.
- A SMAD-independent signaling pathway mediated by TβRI/TβRIII, TRAF6, TAK1, and p38 was activated, causing defective palatal mesenchyme cell proliferation.
- Haploinsufficiency of Tgfb2, Tgfbr1, or Tak1 rescued craniofacial deformities in Tgfbr2 mutant mice by disrupting this noncanonical TGF-β signaling pathway.
Conclusions:
- Activation of a noncanonical TGF-β signaling pathway (TβRI/TβRIII-mediated, SMAD-independent) is responsible for craniofacial malformations in Tgfbr2 mutant mice.
- The identified pathway highlights a critical role for TGF-β signaling in craniofacial development.
- Modulating this specific TGF-β signaling pathway holds potential for preventing congenital craniofacial birth defects.
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