title: An atypical canonical bone morphogenetic protein (BMP) signaling pathway regulates Msh homeobox 1 (Msx1) expression during odontogenesis.
abstract: Bone morphogenetic protein (BMP) signaling plays an essential role in early tooth development, evidenced by disruption of BMP signaling leading to an early arrested tooth development. Despite being a central mediator of BMP canonical signaling pathway, inactivation of Smad4 in dental mesenchyme does not result in early developmental defects. In the current study, we investigated the mechanism of receptor-activated Smads (R-Smads) and Smad4 in the regulation of the odontogenic gene Msx1 expression in the dental mesenchyme. We showed that the canonical BMP signaling is not operating in the early developing tooth, as assessed by failed activation of the BRE-Gal transgenic allele and the absence of phospho-(p)Smad1/5/8-Smad4 complexes. The absence of pSmad1/5/8-Smad4 complex appeared to be the consequence of saturation of Smad4 by pSmad2/3 in the dental mesenchyme as knockdown of Smad2/3 or overexpression of Smad4 led to the formation of pSmad1/5/8-Smad4 complexes and activation of canonical BMP signaling in dental mesenchymal cells. We showed that Smad1/5 but not Smad4 are required for BMP-induced expression of Msx1 in dental mesenchymal cells. We further presented evidence that in the absence of Smad4, BMPs are still able to induce pSmad1/5/8 nuclear translocation and their binding to the Msx1 promoter directly in dental mesenchymal cells. Our results demonstrate the functional operation of an atypical canonical BMP signaling (Smad4-independent and Smad1/5/8-dependent) pathway in the dental mesenchyme during early odontogenesis, which may have general implication in the development of other organs.
authors.affiliation: From the State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China, the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and.
authors.forename: Guobin
authors.initials: G
authors.lastname: Yang
authors.affiliation: From the State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei Province, China, the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and.
authors.forename: Guohua
authors.initials: G
authors.lastname: Yuan
authors.affiliation: the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and.
authors.forename: Wenduo
authors.initials: W
authors.lastname: Ye
authors.affiliation: the Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, California 92697.
authors.forename: Ken W Y
authors.initials: KW
authors.lastname: Cho
authors.affiliation: the Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, and ychen@tulane.edu.
authors.forename: YiPing
authors.initials: Y
authors.lastname: Chen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000483:Alleles; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D051957:MSX1 Transcription Factor / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009805:Odontogenesis / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D014070:Tooth / Q000196:embryology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019076:Transgenes
chemical_list: D019485:Bone Morphogenetic Proteins; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D053773:Transforming Growth Factor beta1
keywords: Bone Morphogenetic Protein (BMP); Cell Signaling; Craniofacial Development; Dental Mesenchyme; Gene Expression; Msx1; SMAD Transcription Factor; Smad4-independent