TGFβ regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate.
Clefting of the soft palate occurs as a congenital defect in humans and adversely affects the physiological function of the palate. However, the molecular and cellular mechanism of clefting of the soft palate remains unclear because few animal models exhibit an isolated cleft in the soft palate. Using three-dimensional microCT images and histological reconstruction, we found that loss of TGFβ signaling in the palatal epithelium led to soft palate muscle defects in Tgfbr2(fl/fl);K14-Cre mice. Specifically, muscle mass was decreased in the soft palates of Tgfbr2 mutant mice, following defects in cell proliferation and differentiation. Gene expression of Dickkopf (Dkk1 and Dkk4), negative regulators of WNT-β-catenin signaling, is upregulated in the soft palate of Tgfbr2(fl/fl);K14-Cre mice, and WNT-β-catenin signaling is disrupted in the palatal mesenchyme. Importantly, blocking the function of DKK1 and DKK4 rescued the cell proliferation and differentiation defects in the soft palate of Tgfbr2(fl/fl);K14-Cre mice. Thus, our findings indicate that loss of TGFβ signaling in epithelial cells compromises activation of WNT signaling and proper muscle development in the soft palate through tissue-tissue interactions, resulting in a cleft soft palate. This information has important implications for prevention and non-surgical correction of cleft soft palate.
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
Jun-ichi
J
Iwata
Akiko
A
Suzuki
Toshiaki
T
Yokota
Thach-Vu
TV
Ho
Richard
R
Pelikan
Mark
M
Urata
Pedro A
PA
Sanchez-Lara
Yang
Y
Chai
D000818:Animals; D002972:Cleft Palate / Q000209:etiology / Q000503:physiopathology*; D017931:DNA Primers / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D021621:Imaging, Three-Dimensional; D015151:Immunoblotting; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D018482:Muscle, Skeletal / Q000196:embryology*; D010160:Palate, Soft / Q000196:embryology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D055114:X-Ray Microtomography
D017931:DNA Primers; C501127:Dkk1 protein, mouse; C513131:Dkk4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
Cleft soft palate; Epithelial-mesenchymal interactions; Mouse; TGFβ