RESUMEN
Binding sites for transcription factor nuclear factor one (NFI) proteins, encoded by four genes in the mouse, have been characterized from many tissue-specific genes. NFI genes are expressed in unique but overlapping patterns in embryonic and in adult tissues. Nfib is highly expressed in the embryonic lung. Here we show that Nfib null mutants die early postnatally and display severe lung hypoplasia. Heterozygotes do survive, but exhibit delayed pulmonary differentiation. Expression of transforming growth factor beta 1 (TGF-beta1) and sonic hedgehog (Shh) is not down-regulated in mutant lung epithelium at late stages of morphogenesis, which may result in incomplete lung maturation. Our study demonstrates that Nfib is essential for normal lung development, and suggests that it could be involved in the pathogenesis of respiratory distress syndromes in humans.
Asunto(s)
Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Proteínas/genética , Proteínas/fisiología , Alelos , Animales , Sitios de Unión , Diferenciación Celular , ADN Complementario/metabolismo , Regulación hacia Abajo , Regulación del Desarrollo de la Expresión Génica , Vectores Genéticos , Proteínas Hedgehog , Inmunohistoquímica , Hibridación in Situ , Pulmón/embriología , Ratones , Modelos Genéticos , Mutación , Factores de Transcripción NFI , Unión Proteica , Estructura Terciaria de Proteína , Recombinación Genética , Transactivadores/biosíntesisRESUMEN
Transcription factor Nuclear Factor One (NFI) proteins are derived from a small family of four vertebrate genes (NFIA, B, C and X), all of which produce a fair number of protein variants by alternative splicing. In order to ultimately locate RNA signal sequences around exon/intron borders for the production of regulated splice variants, we have determined the exon structure of the chicken NFIB gene as the last of the four vertebrate genes for which the gene structure was not yet elucidated. This made it possible to compile nine newly isolated and sequenced mouse NFI cDNA sequences together with all previously available ones and to deduce corresponding splicing patterns for the orthologous vertebrate genes of all four paralogous gene types. Results from the analysis of alternative splicing and of NFI gene mapping in the genome of human and mouse argue for a phylogenetic route in which the four vertebrate NFI genes result from a single duplication of a genomic segment containing two NFI intermediate genes rather than from two independent duplications of two separated single ancestor genes.