RESUMEN
The thymus is a vertebrate-specific organ where T lymphocytes are generated. Genetic programs that lead to thymus development are incompletely understood. We previously screened ethylnitrosourea-induced medaka mutants for recessive defects in thymus development. Here we report that one of those mutants is caused by a missense mutation in a gene encoding the previously uncharacterized protein WDR55 carrying the tryptophan-aspartate-repeat motif. We find that WDR55 is a novel nucleolar protein involved in the production of ribosomal RNA (rRNA). Defects in WDR55 cause aberrant accumulation of rRNA intermediates and cell cycle arrest. A mutation in WDR55 in zebrafish also leads to analogous defects in thymus development, whereas WDR55-null mice are lethal before implantation. These results indicate that WDR55 is a nuclear modulator of rRNA synthesis, cell cycle progression, and embryonic organogenesis including teleost thymus development.
Asunto(s)
Ciclo Celular , Proteínas de Peces/metabolismo , Proteínas Nucleares/metabolismo , Oryzias/crecimiento & desarrollo , Oryzias/metabolismo , ARN Ribosómico/biosíntesis , Timo/crecimiento & desarrollo , Secuencia de Aminoácidos , Animales , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Proteínas de Peces/genética , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Mutación Missense , Células 3T3 NIH , Proteínas Nucleares/genética , Oryzias/genética , Fenotipo , Procesamiento Postranscripcional del ARN , ARN Ribosómico/genética , Alineación de Secuencia , Timo/metabolismo , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismoRESUMEN
The thymus is an organ where T lymphocytes develop. Thymus development requires interactions of cells derived from three germ layers. However, the molecular mechanisms that control thymus development are not fully understood. To identify the genes that regulate thymus development, we previously carried out a large-scale screening for ethylnitrosourea-induced mutagenesis using medaka, Oryzias latipes, and established a panel of recessive thymus-lacking mutants. Here we report the identification of three genes responsible for these mutations. We found that the mutations in KIAA1440, TRRAP, and SKIV2L2 caused the defects in distinct steps of thymus development. We also found that these genes were widely expressed in many organs and that the mutations in these genes caused defects in the development of various other organs. These results enabled us to identify previously unknown roles of widely expressed genes in medaka organ development. The possible reasons why thymus-defective teleost mutants could be used to identify widely expressed genes and future strategies to increase the likelihood of identifying genes that specifically regulate thymus development are discussed.