RESUMEN
The Transforming growth factor ß (Tgf-ß) pathway, by signaling via the activation of Smad transcription factors, induces the expression of many diverse downstream target genes thereby regulating a vast array of cellular events essential for proper development and homeostasis. In order for a specific cell type to properly interpret the Tgf-ß signal and elicit a specific cellular response, cell-specific transcriptional co-factors often cooperate with the Smads to activate a discrete set of genes in the appropriate temporal and spatial manner. Here, via a conditional knockout approach, we show that mice mutant for Forkhead Box O transcription factor FoxO1 exhibit an enamel hypomaturation defect which phenocopies that of the Smad3 mutant mice. Furthermore, we determined that both the FoxO1 and Smad3 mutant teeth exhibit changes in the expression of similar cohort of genes encoding enamel matrix proteins required for proper enamel development. These data raise the possibility that FoxO1 and Smad3 act in concert to regulate a common repertoire of genes necessary for complete enamel maturation. This study is the first to define an essential role for the FoxO family of transcription factors in tooth development and provides a new molecular entry point which will allow researchers to delineate novel genetic pathways regulating the process of biomineralization which may also have significance for studies of human tooth diseases such as amelogenesis imperfecta.
Asunto(s)
Amelogénesis/genética , Esmalte Dental/metabolismo , Factores de Transcripción Forkhead/fisiología , Calcificación de Dientes/genética , Animales , Calcificación Fisiológica/genética , Calcificación Fisiológica/fisiología , Esmalte Dental/crecimiento & desarrollo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Pruebas de Dureza , Integrasas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína smad3/genética , Proteína smad3/metabolismo , Proteína smad3/fisiología , Enfermedades Dentales/genética , Enfermedades Dentales/patología , Factores de Transcripción/genética , Factores de Transcripción/fisiologíaRESUMEN
Heterotopic ossification (HO), or endochondral bone formation at nonskeletal sites, often results from traumatic injury and can lead to devastating consequences. Alternatively, the ability to harness this phenomenon would greatly enhance current orthopedic tools for treating segmental bone defects. Thus, understanding the earliest events in this process potentially would allow us to design more targeted therapies to either block or enhance this process. Using a murine model of HO induced by delivery of adenovirus-transduced cells expressing bone morphogenetic protein 2 (BMP-2), we show here that one of the earliest stages in this process is the establishment of new vessels prior to the appearance of cartilage. As early as 48 hours after induction of HO, we observed the appearance of brown adipocytes expressing vascular endothelial growth factors (VEGFs) simultaneous with endothelial progenitor replication. This was determined by using a murine model that possesses the VEGF receptor 2 (Flk1) promoter containing an endothelial cell enhancer driving the expression of nuclear-localized yellow fluorescent protein (YFP). Expression of this marker has been shown previously to correlate with the establishment of new vasculature, and the nuclear localization of YFP expression allowed us to quantify changes in endothelial cell numbers. We found a significant increase in Flk1-H2B::YFP cells in BMP-2-treated animals compared with controls. The increase in endothelial progenitors occurred 3 days prior to the appearance of early cartilage. The data collectively suggest that vascular remodeling and growth may be essential to modify the microenvironment and enable engraftment of the necessary progenitors to form endochondral bone.
Asunto(s)
Proteína Morfogenética Ósea 2/farmacología , Cartílago/irrigación sanguínea , Osificación Heterotópica/metabolismo , Adipocitos Marrones/metabolismo , Animales , Antígeno Ki-67/biosíntesis , Ratones , ARN Mensajero/metabolismo , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Factor de von Willebrand/biosíntesisRESUMEN
Development of the coronary vascular system is an interesting model in developmental biology with major implications for the clinical setting. Although coronary vessel development is a form of vasculogenesis followed by angiogenesis, this system uses several unique developmental processes not observed in the formation of other blood vessels. This review summarizes the literature that describes the development of the coronary system, highlighting the unique aspects of coronary vessel development. It should be noted that many of the basic mechanisms that govern vasculogenesis in other systems have not been analyzed in coronary vessel development. In addition, we present recent advances in the field that uncover the basic mechanisms regulating the generation of these blood vessels and identify areas in need of additional studies.
Asunto(s)
Vasos Coronarios/embriología , Vasos Coronarios/crecimiento & desarrollo , Neovascularización Fisiológica/fisiología , Animales , Vasos Coronarios/fisiología , HumanosRESUMEN
Recent work has demonstrated the importance of the epicardium in the development of the heart. During embryogenesis, these epithelial cells provide the progenitors for the epicardium, coronary smooth muscle, endothelium, and cardiac fibroblasts. The epicardium sends important signals to the developing myocardium. Still, analysis of these epithelial cells has lagged behind that of other cardiac cell types largely because of the lack of a defined experimental cell system in which epicardial cell differentiation can be studied. The present report examines the developmental potential of a cell line derived from rat epicardial mesothelial cells. These analyses demonstrate that the cell line retains many characteristics of the intact epithelium, including the ability to form a polarized epithelium and express many epicardial genes. Our data show for the first time that these cells retain the ability to produce mesenchyme in response to specific growth factors and, importantly, to generate smooth muscle cells. Thus, this study provides evidence that these cells can serve as an important model system for the analysis of the cellular and molecular mechanisms that govern epicardial development and function.