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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.

In vivo imaging of thymocytes has not been accomplished due to their localization deep within opaque body and high susceptibility to surgical stress. To overcome these problems, medaka is useful because of transparency and ex-uterine development. We report the noninvasive detection of thymocytes in transgenic medaka that express fluorescent protein under the control of immature-lymphocyte-specific rag1. We show that lymphoid progenitor cells colonize the thymus primordium in an anterior-to-posterior orientation-specific manner, revealing that extrathymic anterior components guide prevascular thymus colonization. We also show that developing thymocytes acquire “random walk motility” along with the expression of Ag receptors and coreceptors, suggesting that thymocyte walking is initiated at the developmental stage for repertoire selection. Thus, transgenic medaka enables real-time intravital imaging of thymocytes without surgical invasion.

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.

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., Author Summary Medaka, Oryzias latipes, is a small freshwater fish that is useful for studies of forward and reverse genetics. The availability of various inbred strains is the distinct advantage of medaka over zebrafish, especially in studies of the immune system. The thymus is a primary immune organ that is unique to vertebrates and supports the generation of T lymphocytes. Defective thymus development tends to cause abnormal T lymphocyte development, resulting in immunodeficiency or autoimmunity. However, the molecular pathways underlying thymus development have not been fully uncovered. Here we report the positional cloning of a gene responsible for one of the thymus-defective medaka mutants. We find that the hkc phenotype is caused by a missense mutation in a gene encoding the previously uncharacterized protein WDR55. Our results indicate that WDR55 is a novel nucleolar modulator of rRNA biosynthesis, cell cycle progression, and vertebrate development of organs, including teleost thymus. These results not only provide evidence of the existence of a new mechanism of rRNA production but also demonstrate that the malfunction of WDR55 causes cell cycle arrest and developmental failure, including defective thymus development.