RESUMO
During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the homeodomain factor Nkx2-5. We now show that feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology. In the cardiac fields of Nkx2-5 mutants, genes controlling cardiac specification (including Bmp2) and maintenance of the progenitor state were upregulated, leading initially to progenitor overspecification, but subsequently to failed SHF proliferation and OFT truncation. In Smad1 mutants, SHF proliferation and deployment to the OFT were increased, while Smad1 deletion in Nkx2-5 mutants rescued SHF proliferation and OFT development. In Nkx2-5 hypomorphic mice, which recapitulate human congenital heart disease (CHD), OFT anomalies were also rescued by Smad1 deletion. Our findings demonstrate that Nkx2-5 orchestrates the transition between periods of cardiac induction, progenitor proliferation, and OFT morphogenesis via a Smad1-dependent negative feedback loop, which may be a frequent molecular target in CHD.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Retroalimentação Fisiológica , Proteínas de Homeodomínio/metabolismo , Células-Tronco Multipotentes/citologia , Miocárdio/citologia , Miócitos Cardíacos/citologia , Proteína Smad1/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Proteína Morfogenética Óssea 2 , Proliferação de Células , DNA Complementar , Embrião de Mamíferos , Coração/embriologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Proteínas com Homeodomínio LIM , Camundongos , Células-Tronco Multipotentes/metabolismo , Miócitos Cardíacos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Fatores de Transcrição/genéticaRESUMO
The mammalian gastrointestinal tract is covered by a layer of mucus that can harbour a range of bacterial species specifically adapted to colonize this ecological niche. Examination of 110 bacterial isolates cultivated from the gastrointestinal tract of 23 mice revealed the presence of a subgroup of 30 isolates that did not correspond genetically with genera commonly associated with this site, i.e. members of the epsilon-Proteobacteria such as Helicobacter and Campylobacter species. Instead this group of isolates was found to lie within the phylum Deferribacteres, a completely distinct lineage in the domain Bacteria. There was a high level of consensus in results obtained from the phenotypic and genotypic characterization of a number of the isolates, which showed they were distinct from other members of the Deferribacteres. As such, they are proposed to constitute a new genus and species, Mucispirillum schaedleri gen. nov., sp. nov. These organisms are anaerobic, Gram-negative, spiral-shaped rods with bipolar flagella. The type strain is HRI I17(T) (= ATCC BAA-1009(T) = ACM 5223(T)).
