Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Dev Dyn ; 248(3): 233-246, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30620790

RESUMO

BACKGROUND: Bent bone dysplasia syndrome (BBDS), a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2), is characterized by bowed long bones within the limbs. We previously showed that the FGFR2 mutations in BBDS enhance nuclear and nucleolar localization of the receptor; however, exactly how shifts in subcellular distribution of FGFR2 affect limb development remained unknown. RESULTS: Targeted expression of the BBDS mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, a hallmark feature of the disease. Whole-mount analysis of the underlying skeleton revealed bent long bones with shortened bone collars and, in severe cases, dysmorphic epiphyses. Epiphyseal changes were also correlated with joint dislocations and contractures. Histological analysis revealed that bent long bones and joint defects were closely associated with irregularities in skeletal muscle patterning and tendon-to-bone attachment. The spectrum of limb phenotypes induced by the BBDS mutations were recapitulated by targeted expression of wild-type FGFR2 appended with nuclear and nucleolar localization signals. CONCLUSIONS: Our results indicate that the bent long bones in BBDS arise from disruptions in musculoskeletal integration and that increased nuclear and nucleolar localization of FGFR2 plays a mechanistic role in the disease phenotype. 248:233-246, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Núcleo Celular/química , Extremidades/crescimento & desenvolvimento , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Embrião de Galinha , Deformidades Congênitas dos Membros/genética , Fenótipo , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia
2.
Dev Dyn ; 246(4): 262-274, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27859991

RESUMO

Here we review studies identifying regulatory networks responsible for synovial, cartilaginous, and fibrous joint development. Synovial joints, characterized by the fluid-filled synovial space between the bones, are found in high-mobility regions and are the most common type of joint. Cartilaginous joints such as the intervertebral disc unite adjacent bones through either a hyaline cartilage or a fibrocartilage intermediate. Fibrous joints, which include the cranial sutures, form a direct union between bones through fibrous connective tissue. We describe how the distinct morphologic and histogenic characteristics of these joint classes are established during embryonic development. Collectively, these studies reveal that despite the heterogeneity of joint strength and mobility, joint development throughout the skeleton utilizes common signaling networks via long-range morphogen gradients and direct cell-cell contact. This suggests that different joint types represent specialized variants of homologous developmental modules. Identifying the unifying aspects of the signaling networks between joint classes allows a more complete understanding of the signaling code for joint formation, which is critical to improving strategies for joint regeneration and repair. Developmental Dynamics 246:262-274, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Articulações/crescimento & desenvolvimento , Transdução de Sinais/fisiologia , Animais , Cartilagem Articular , Redes Reguladoras de Genes , Humanos , Cápsula Articular , Articulações/anatomia & histologia , Articulações/embriologia , Morfogênese , Regeneração
3.
Hum Mol Genet ; 23(21): 5659-71, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24908667

RESUMO

Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by de-repressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.


Assuntos
Acrocefalossindactilia/genética , Acrocefalossindactilia/metabolismo , Núcleo Celular/metabolismo , DNA Ribossômico/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transcrição Gênica , Animais , Sítios de Ligação , Diferenciação Celular , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Mutação , Osteoblastos/citologia , Osteoblastos/metabolismo , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Ligação Proteica , Transporte Proteico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Sequências Repetitivas de Ácido Nucleico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...