RESUMO
The phylogenetically conserved nuclear factor I (NFI) family of transcription/replication proteins is essential both for adenoviral DNA replication and for the transcription of many cellular genes. We showed previously that the four murine NFI genes (Nfia, Nfib, Nfic, and Nfix) are expressed in unique but overlapping patterns during mouse development and in adult tissues. Here we show that disruption of the Nfia gene causes perinatal lethality, with >95% of homozygous Nfia(-/-) animals dying within 2 weeks after birth. Newborn Nfia(-/-) animals lack a corpus callosum and show ventricular dilation indicating early hydrocephalus. Rare surviving homozygous Nfia(-/-) mice lack a corpus callosum, show severe communicating hydrocephalus, a full-axial tremor indicative of neurological defects, male-sterility, low female fertility, but near normal life spans. These findings indicate that while the Nfia gene appears nonessential for cell viability and DNA replication in embryonic stem cells and fibroblasts, loss of Nfia function causes severe developmental defects. This finding of an NFI gene required for a developmental process suggests that the four NFI genes may have distinct roles in vertebrate development.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT , Corpo Caloso/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Hidrocefalia/genética , Fatores de Transcrição , Animais , Encéfalo/metabolismo , Feminino , Fertilidade/genética , Fibroblastos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Genéticos , Mutagênese , Fatores de Transcrição NFI , Proteínas Nucleares , Fenótipo , Recombinação Genética , Células-Tronco/metabolismo , Proteína 1 de Ligação a Y-BoxRESUMO
The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The somewhat different phenotypes of fa/fa and cp/cp animals probably reflect the fact that the mutations are segregating on different rat strains. The fa mutation has been mapped to the interval between Pgm1 and Glut1 on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LA/N-BN cp/+ intercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glut1 and Pgm1: Pgm1-------- cp -------- Glut1 map distance (cM) 1.67 6.67 Thus, cp and fa map to the same approximately 8 cm interval of the rat genome. In conjunction with the complementation studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr).
