Document Detail


SMAD4-mediated WNT signaling controls the fate of cranial neural crest cells during tooth morphogenesis.
MedLine Citation:
PMID:  21490069     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
TGFβ/BMP signaling regulates the fate of multipotential cranial neural crest (CNC) cells during tooth and jawbone formation as these cells differentiate into odontoblasts and osteoblasts, respectively. The functional significance of SMAD4, the common mediator of TGFβ/BMP signaling, in regulating the fate of CNC cells remains unclear. In this study, we investigated the mechanism of SMAD4 in regulating the fate of CNC-derived dental mesenchymal cells through tissue-specific inactivation of Smad4. Ablation of Smad4 results in defects in odontoblast differentiation and dentin formation. Moreover, ectopic bone-like structures replaced normal dentin in the teeth of Osr2-IresCre;Smad4(fl/fl) mice. Despite the lack of dentin, enamel formation appeared unaffected in Osr2-IresCre;Smad4(fl/fl) mice, challenging the paradigm that the initiation of enamel development depends on normal dentin formation. At the molecular level, loss of Smad4 results in downregulation of the WNT pathway inhibitors Dkk1 and Sfrp1 and in the upregulation of canonical WNT signaling, including increased β-catenin activity. More importantly, inhibition of the upregulated canonical WNT pathway in Osr2-IresCre;Smad4(fl/fl) dental mesenchyme in vitro partially rescued the CNC cell fate change. Taken together, our study demonstrates that SMAD4 plays a crucial role in regulating the interplay between TGFβ/BMP and WNT signaling to ensure the proper CNC cell fate decision during organogenesis.
Authors:
Jingyuan Li; Xiaofeng Huang; Xun Xu; Julie Mayo; Pablo Bringas; Rulang Jiang; Songling Wang; Yang Chai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-04-13
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  138     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-27     Completed Date:  2011-07-01     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  1977-89     Citation Subset:  IM    
Affiliation:
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
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MeSH Terms
Descriptor/Qualifier:
Ameloblasts / cytology,  metabolism
Animals
Cell Differentiation / genetics,  physiology
Cell Lineage / genetics,  physiology
Dental Enamel / embryology
Dentin / embryology
Female
Gene Expression Regulation, Developmental
Intercellular Signaling Peptides and Proteins / genetics,  metabolism
Male
Membrane Proteins / metabolism
Mice
Mice, Knockout
Mice, Transgenic
Neural Crest / cytology,  embryology*,  metabolism
Odontoblasts / cytology,  metabolism
Odontogenesis / genetics,  physiology*
Pregnancy
Signal Transduction
Smad4 Protein / deficiency,  genetics,  physiology*
Tooth / cytology,  embryology*,  metabolism
Wnt Proteins / physiology*
Grant Support
ID/Acronym/Agency:
R37 DE012711/DE/NIDCR NIH HHS; U01 DE020065/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Dkk1 protein, mouse; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Sfrp1 protein, mouse; 0/Smad4 Protein; 0/Smad4 protein, mouse; 0/Wnt Proteins
Comments/Corrections

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