RESUMEN
The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7(Mtu) and Rps7(Zma)) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes.
Asunto(s)
Anemia de Diamond-Blackfan , Sistema Nervioso Central , Morfogénesis/genética , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/patología , Animales , Tamaño Corporal/genética , Sistema Nervioso Central/crecimiento & desarrollo , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Humanos , Memoria a Corto Plazo/fisiología , Ratones , Mutación , Fenotipo , Proteínas Ribosómicas/fisiología , Ribosomas/genéticaRESUMEN
Melanoblasts are a population of neural crest-derived cells that generate the pigment-producing cells of our body. Defective melanoblast development and function underlies many disorders including Waardenburg syndrome and melanoma. Understanding the genetic regulation of melanoblast development will help elucidate the etiology of these and other neurocristopathies. Here we demonstrate that Magoh, a component of the exon junction complex, is required for normal melanoblast development. Magoh haploinsufficient mice are hypopigmented and exhibit robust genetic interactions with the transcription factor, Sox10. These phenotypes are caused by a marked reduction in melanoblast number beginning at mid-embryogenesis. Strikingly, while Magoh haploinsufficiency severely reduces epidermal melanoblasts, it does not significantly affect the number of dermal melanoblasts. These data indicate Magoh impacts melanoblast development by disproportionately affecting expansion of epidermal melanoblast populations. We probed the cellular basis for melanoblast reduction and discovered that Magoh mutant melanoblasts do not undergo increased apoptosis, but instead are arrested in mitosis. Mitotic arrest is evident in both Magoh haploinsufficient embryos and in Magoh siRNA treated melanoma cell lines. Together our findings indicate that Magoh-regulated proliferation of melanoblasts in the dermis may be critical for production of epidermally-bound melanoblasts. Our results point to a central role for Magoh in melanocyte development.
Asunto(s)
Exones/genética , Melanocitos/metabolismo , Melanocitos/patología , Cresta Neural/patología , Proteínas Nucleares/metabolismo , Animales , Tipificación del Cuerpo/genética , Recuento de Células , Línea Celular , Proliferación Celular , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Puntos de Control de la Fase G2 del Ciclo Celular , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Haploinsuficiencia/genética , Hipopigmentación/embriología , Hipopigmentación/genética , Hipopigmentación/patología , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Mitosis , Proteínas Nucleares/genética , Factores de Transcripción SOXE/genéticaRESUMEN
The differentiation of activated CD4(+) T cells into the T helper type 1 (T(H)1) or T(H)2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3. Whereas interleukin 12 (IL-12) produced by antigen-presenting cells initiates the T(H)1 fate, signals that initiate the T(H)2 fate are not completely characterized. Here we show that early GATA-3 expression, required for T(H)2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor beta-catenin, mainly from the proximal Gata3 promoter upstream of exon 1b. This activity was induced after T cell antigen receptor (TCR) stimulation and was independent of IL-4 receptor signaling through the transcription factor STAT6. Furthermore, TCF-1 blocked T(H)1 fate by negatively regulating interferon-gamma (IFN-gamma) expression independently of beta-catenin. Thus, TCF-1 initiates T(H)2 differentiation of activated CD4(+) T cells by promoting GATA-3 expression and suppressing IFN-gamma expression.