TY - JOUR A1 - Anelli, Viviana A1 - Ordas, Anita A1 - Kneitz, Susanne A1 - Sagredo, Leonel Munoz A1 - Gourain, Victor A1 - Schartl, Manfred A1 - Meijer, Annemarie H. A1 - Mione, Marina T1 - Ras-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression JF - Frontiers in Genetics N2 - Ras genes are among the most commonly mutated genes in human cancer; yet our understanding of their oncogenic activity at the molecular mechanistic level is incomplete. To identify downstream events that mediate ras-induced cellular transformation in vivo, we analyzed global microRNA expression in three different models of Ras-induction and tumor formation in zebrafish. Six microRNAs were found increased in Ras-induced melanoma, glioma and in an inducible model of ubiquitous Ras expression. The upregulation of the microRNAs depended on the activation of the ERK and AKT pathways and to a lesser extent, on mTOR signaling. Two Ras-induced microRNAs (miR-146a and 193a) target Jmjd6, inducing downregulation of its mRNA and protein levels at the onset of Ras expression during melanoma development. However, at later stages of melanoma progression, jmjd6 levels were found elevated. The dynamic of Jmjd6 levels during progression of melanoma in the zebrafish model suggests that upregulation of the microRNAs targeting Jmjd6 may be part of an anti-cancer response. Indeed, triple transgenic fish engineered to express a microRNA-resistant Jmjd6 from the onset of melanoma have increased tumor burden, higher infiltration of leukocytes and shorter melanoma-free survival. Increased JMJD6 expression is found in several human cancers, including melanoma, suggesting that the up-regulation of Jmjd6 is a critical event in tumor progression. The following link has been created to allow review of record GSE37015: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jjcrbiuicyyqgpc&acc=GSE37015. KW - zebrafish KW - cancer models KW - microRNA KW - Jmjd6 KW - ras KW - melanoma KW - miR-146a KW - miR-193a Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196963 SN - 1664-8021 VL - 9 IS - 675 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Herpin, Amaury A1 - Martinez-Bengochea, Anabel A1 - Kneitz, Susanne A1 - Regensburger, Martina A1 - Grunwald, David J. A1 - Schartl, Manfred T1 - Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka JF - Frontiers in Cell and Developmental Biology N2 - Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes. KW - sex determination KW - retinoic acid KW - meiosis KW - gametogenesis KW - medaka Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222669 SN - 2296-634X VL - 8 ER - TY - JOUR A1 - Adolfi, Mateus C. A1 - Du, Kang A1 - Kneitz, Susanne A1 - Cabau, Cédric A1 - Zahm, Margot A1 - Klopp, Christophe A1 - Feron, Romain A1 - Paixão, Rômulo V. A1 - Varela, Eduardo S. A1 - de Almeida, Fernanda L. A1 - de Oliveira, Marcos A. A1 - Nóbrega, Rafael H. A1 - Lopez-Roques, Céline A1 - Iampietro, Carole A1 - Lluch, Jérôme A1 - Kloas, Werner A1 - Wuertz, Sven A1 - Schaefer, Fabian A1 - Stöck, Matthias A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - A duplicated copy of id2b is an unusual sex-determining candidate gene on the Y chromosome of arapaima (Arapaima gigas) JF - Scientific Reports N2 - Arapaima gigas is one of the largest freshwater fish species of high ecological and economic importance. Overfishing and habitat destruction are severe threats to the remaining wild populations. By incorporating a chromosomal Hi-C contact map, we improved the arapaima genome assembly to chromosome-level, revealing an unexpected high degree of chromosome rearrangements during evolution of the bonytongues (Osteoglossiformes). Combining this new assembly with pool-sequencing of male and female genomes, we identified id2bbY, a duplicated copy of the inhibitor of DNA binding 2b (id2b) gene on the Y chromosome as candidate male sex-determining gene. A PCR-test for id2bbY was developed, demonstrating that this gene is a reliable male-specific marker for genotyping. Expression analyses showed that this gene is expressed in juvenile male gonads. Its paralog, id2ba, exhibits a male-biased expression in immature gonads. Transcriptome analyses and protein structure predictions confirm id2bbY as a prime candidate for the master sex-determiner. Acting through the TGF beta signaling pathway, id2bbY from arapaima would provide the first evidence for a link of this family of transcriptional regulators to sex determination. Our study broadens our current understanding about the evolution of sex determination genetic networks and provide a tool for improving arapaima aquaculture for commercial and conservation purposes. KW - evolutionary genetics KW - genetic markers KW - genome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265672 VL - 11 IS - 1 ER -