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.

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 ethylnitrosoureainduced 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.Key words: Ethylnitrosourea-induced mutagenesis . Medaka . Organogenesis .Positional cloning . Thymus Supporting Information available online IntroductionThe thymus is an organ where T lymphocytes develop and is necessary for the generation of a highly developed immune system in vertebrates. Thymus generation is initiated by the budding of the third pharyngeal pouch endoderm and its interaction with migrating neural crest cells [1,2]. The thymus primordium is colonized by hematopoietic stem cellderived lymphoid progenitor cells [3,4]. Signals from the lymphoid cells are necessary for the further maturation of the thymus to form distinct regions of the cortex and the medulla [5][6][7]. 2606Genes required for functional thymus development have been extensively investigated using thymus-defective patients and rodent models. The DiGeorge syndrome is a genetic disorder characterized by hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and outflow tract defects of the heart (OMIM 188400) [8]. Most cases of the DiGeorge syndrome are a result of the deletion of chromosome 22q11.2, and tbx1 encoded in this region is responsible for the onset of defective thymus development in many DiGeorge syndrome patients [9,10]. It was also shown that mutations in foxn1 in human and mouse can induce the nude phenotype that is characterized by defective thymus development and hairless caused by defective hair follicles (OMIM 601705) [11,12]. Defects in functional thymus development may sometimes result in autoimmune diseases. For example, mutations in AIRE, which is specifically expressed by a fraction of thymic medullary epithelial cells, cause autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (OMIM 607358) [13]. Nevertheless, the molecular pathways that control thymus development have not been fully elucidated.We previously carried out a l...

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This cover is specifically designed to celebrate the 2nd European Congress of Immunology (www.eci‐berlin2009.com), to be held September 13–16, 2009 in Berlin. The cover consists of a collage of images from Iwanami et al. (pp 2606–2616) with Berlin's historic Bradenburg Gate, Brandenburger Tor, in the forefront (image of the Brandenburg Gate r ImageState'. Iwanami et al.'s elegant study shows that, in addition, to defective thymus development, teleosts with mutations in KIAA1440, TRRAP, and SKIV2L2 also exhibit defective development of multiple organs, thus identifying previously unknown roles of these genes in organ development.