RESUMO
Embryonic cortical neural stem cells apparently have a transient existence, as they do not persist in the adult cortex. We sought to determine the fate of embryonic cortical stem cells by following Emx1(IREScre); LacZ/EGFP double-transgenic murine cells from midgestation into adulthood. Lineage tracing in combination with direct cell labeling and time-lapse video microscopy demonstrated that Emx1-lineage embryonic cortical stem cells migrate ventrally into the striatal germinal zone (GZ) perinatally and intermingle with striatal stem cells. Upon integration into the striatal GZ, cortical stem cells down-regulate Emx1 and up-regulate Dlx2, which is a homeobox gene characteristic of the developing striatum and striatal neural stem cells. This demonstrates the existence of a novel dorsal-to-ventral migration of neural stem cells in the perinatal forebrain.
Assuntos
Movimento Celular , Córtex Cerebral/citologia , Embrião de Mamíferos/citologia , Neurônios/citologia , Células-Tronco/fisiologia , Animais , Gânglios da Base/citologia , Linhagem da Célula , Córtex Cerebral/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteínas de Fluorescência Verde/análise , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia de Vídeo , Fenótipo , Células-Tronco/citologia , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-beta and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)-Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-beta/Wnt cooperative targets. Our results indicate that the TGF-beta and Wnt/beta-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression.
Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Intestinais/genética , Neoplasias Mamárias Experimentais/genética , Fator de Crescimento Transformador beta/genética , Proteínas Wnt/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Células L , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Transcrição Gênica , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Proteína Wnt3RESUMO
Mixl1 is a member of the Mix/Bix family of paired-like homeodomain proteins and is required for proper axial mesendoderm morphogenesis and endoderm formation during mouse development. Mix/Bix proteins are transcription factors that function in Nodal-like signaling pathways and are themselves regulated by Nodal. Here, we show that Foxh1 forms a DNA-binding complex with Smads to regulate transforming growth factor beta (TGFbeta)/Nodal-dependent Mixl1 gene expression. Whereas Foxh1 is commonly described as a transcriptional activator, we observed that Foxh1-null embryos exhibit expanded and enhanced Mixl1 expression during gastrulation, indicating that Foxh1 negatively regulates expression of Mixl1 during early mouse embryogenesis. We demonstrate that Foxh1 associates with the homeodomain-containing protein Goosecoid (Gsc), which in turn recruits histone deacetylases to repress Mixl1 gene expression. Ectopic expression of Gsc in embryoid bodies represses endogenous Mixl1 expression and this effect is dependent on Foxh1. As Gsc is itself induced in a Foxh1-dependent manner, we propose that Foxh1 initiates positive and negative transcriptional circuits to refine cell fate decisions during gastrulation.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteína Goosecoid/metabolismo , Proteínas de Homeodomínio/metabolismo , Ativinas/metabolismo , Animais , Linhagem Celular , Regulação para Baixo , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Proteína Goosecoid/genética , Histona Desacetilases/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Knockout , Proteína Nodal , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Smad/metabolismo , Fatores de Tempo , Transcrição Gênica/genética , Ativação Transcricional/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Transforming growth factor-betas (TGFbeta) and Wnts represent two distinct families of secreted molecules each of which utilizes different signaling pathways to elicit their biological effects. These factors regulate numerous developmental events and mutations in components of both pathways have been described in human cancers including colorectal carcinomas. Several studies have demonstrated that TGFbeta and Wnt ligands can cooperate to regulate differentiation and cell fate determination by controlling gene expression patterns. In addition, their cooperation in promoting tumorigenesis in mice has been described. Here, we focus on reviewing our current understanding of the molecular mechanisms that may mediate these cooperative effects.