RRC ID 37016
Author Otsu K, Ida-Yonemochi H, Fujiwara N, Harada H.
Title The Semaphorin 4D-RhoA-Akt Signal Cascade Regulates Enamel Matrix Secretion in Coordination With Cell Polarization During Ameloblast Differentiation.
Journal J Bone Miner Res
Abstract During tooth development, oral epithelial cells differentiate into ameloblasts in order to form the most mineralized tissue in the vertebrate body: enamel. During this process, ameloblasts directionally secrete enamel matrix proteins and morphologically change from low columnar cells to polarized tall columnar cells, both of which are essential for the proper formation of enamel. In this study, we elucidated the molecular mechanism that integrates ameloblast function and morphology. Immunohistochemistry revealed that the restricted expression of semaphorin 4D (Sema4D) and RhoA activation status are closely associated with ameloblast differentiation in mouse incisors. In addition, in vitro gain-of-function and loss-of-function experiments demonstrated that Sema4D acts upstream of RhoA to regulate cell polarity and amelogenin expression via the Plexin B1/Leukemia-associated RhoGEF (LARG) complex during ameloblast differentiation. Experiments in transgenic mice demonstrated that expression of a dominant-negative form of RhoA in dental epithelium hindered ameloblast differentiation and subsequent enamel formation, as well as perturbing the establishment of polarized cell morphology and vectorial amelogenin expression. Finally, we showed that spatially restricted Akt mediates between Sema4D-RhoA signaling and these downstream cellular events. Collectively, our results reveal a novel signaling network, the Sema4D-RhoA-Akt signal cascade, that coordinates cellular function and morphology and highlights the importance of specific spatiotemporally restricted components of a signaling pathway in the regulation of ameloblast differentiation. © 2016 American Society for Bone and Mineral Research.
Volume 31(11)
Pages 1943-1954
Published 2016-11-1
DOI 10.1002/jbmr.2876
PMID 27218883
MeSH Ameloblasts / cytology* Ameloblasts / metabolism Amelogenin / metabolism Animals Antigens, CD / metabolism* Cell Differentiation* Cell Polarity* Cell Proliferation Dental Enamel / metabolism* Dental Enamel Proteins / metabolism* Humans Mice Models, Biological Nerve Tissue Proteins / metabolism Phenotype Proto-Oncogene Proteins c-akt / metabolism* Receptors, Cell Surface / metabolism Rho Guanine Nucleotide Exchange Factors / metabolism Semaphorins / metabolism* Signal Transduction Tooth / metabolism rhoA GTP-Binding Protein / metabolism*
IF 5.854
Times Cited 1
Mice RBRC01294