RESUMEN
Hypomorphic mutation in one allele of ribosomal protein l24 gene (Rpl24) is responsible for the Belly Spot and Tail (Bst) mouse, which suffers from defects of the eye, skeleton, and coat pigmentation. It has been hypothesized that these pathological manifestations result exclusively from faulty protein synthesis. We demonstrate here that upregulation of the p53 tumor suppressor during the restricted period of embryonic development significantly contributes to the Bst phenotype. However, in the absence of p53 a large majority of Rpl24(Bst/+) embryos die. We showed that p53 promotes survival of these mice via p21-dependent mechanism. Our results imply that activation of a p53-dependent checkpoint mechanism in response to various ribosomal protein deficiencies might also play a role in the pathogenesis of congenital malformations in humans.
Asunto(s)
Anomalías del Ojo/genética , Regulación del Desarrollo de la Expresión Génica , Color del Cabello/genética , Anomalías Musculoesqueléticas/genética , Proteínas Ribosómicas/metabolismo , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Embrión de Mamíferos/anatomía & histología , Embrión de Mamíferos/fisiología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Embarazo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Ribosómicas/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The capacity to detect and appropriately respond to many different stresses that interfere with functional homeostasis is essential for survival. Recent evidence suggests that the nucleolus, the site of ribosome biogenesis, plays a critical role in sensing and responding to both external and internal stresses. To understand these processes, we have recently used a genetically defined in vivo mouse model in which ribosome biogenesis could be manipulated during oogenesis and embryo development. In these mice ribosomal biosynthesis is impaired by a conditional deletion of one allele of the gene encoding 40S ribosomal protein S6. Embryos from these animals fail during gastrulation, apparently due to a p53-dependent checkpoint being triggered, rather than a deficit in translational capacity. These findings imply that molecular mechanisms have evolved during mammalian evolution to strongly guard against potential heterozygosity for ribosomal protein genes.