Ectodermal Smad4 and p38 MAPK are functionally redundant in mediating TGF-beta/BMP signaling during tooth and palate development.
Smad4 is a central intracellular effector of TGF-beta signaling. Smad-independent TGF-beta pathways, such as those mediated by p38 MAPK, have been identified in cell culture systems, but their in vivo functional mechanisms remain unclear. In this study, we investigated the role of TGF-beta signaling in tooth and palate development and noted that conditional inactivation of Smad4 in oral epithelium results in much milder phenotypes than those seen with the corresponding receptor mutants, Bmpr1a and Tgfbr2, respectively. Perturbed p38 function in these tissues likewise has no effect by itself; however, when both Smad4 and p38 functions are compromised, dramatic recapitulation of the receptor mutant phenotypes results. Thus, our study demonstrates that p38 and Smad4 are functionally redundant in mediating TGF-beta signaling in diverse contexts during embryonic organogenesis. The ability of epithelium to utilize both pathways illustrates the complicated nature of TGF-beta signaling mechanisms in development and disease.
Xu
Xun
X
Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Han
Jun
J
Ito
Yoshihiro
Y
Bringas
Pablo
P
Deng
Chuxia
C
Chai
Yang
Y
D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004475:Ectoderm / Q000201:enzymology*; D004789:Enzyme Activation; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D010159:Palate / Q000196:embryology* / Q000201:enzymology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D014070:Tooth / Q000196:embryology* / Q000201:enzymology; D014071:Tooth Abnormalities; D014083:Tooth Germ / Q000196:embryology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C045073:Cre recombinase; D019426:Integrases