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1.
PLoS Genet ; 10(1): e1004145, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24497849

RESUMO

WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation.


Assuntos
Complexos Multiproteicos/genética , Osteogênese/genética , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/genética , Proteínas Wnt/genética , Animais , Diferenciação Celular , Linhagem da Célula , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/biossíntese , Osteoblastos/citologia , Proteínas Proto-Oncogênicas/biossíntese , Serina-Treonina Quinases TOR/biossíntese , Proteínas Wnt/biossíntese , Via de Sinalização Wnt , Proteína Wnt-5a
2.
J Mol Cell Biol ; 7(5): 441-54, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26243590

RESUMO

The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration.


Assuntos
Fator 8 de Crescimento de Fibroblasto/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Crista Neural/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Fator 8 de Crescimento de Fibroblasto/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genótipo , Humanos , Imuno-Histoquímica , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
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