Posttranskriptionelle Regulation von Dmrt1 bei der Geschlechtsentwicklung in Medaka
Allgemeine Genetik und funktionelle Genomforschung
Zellbiologie
Zusammenfassung der Projektergebnisse
Main issues raised & general objectives. The gonads of vertebrates are characterized by the intimate association of germ cells and supporting somatic cell. The precursor cells of the soma are derived from the embryonic lateral plate mesoderm whereas germ cells originate from the germline lineage. To carry out their highly specialized biological functions, the somatic gonadal primordium and the germline cells together must establish timely regulated programs of gene expression. Dmrt1 is a highly conserved transcription factor, which is critically involved in regulation of gonad development of vertebrates. In medaka a Y-chromosome specific duplicate of dmrt1, acts as the master male sexdetermining gene. It has a tightly timely and spatially controlled gonadal expression pattern during development. We found previously that in addition to transcriptional regulation, a sequence motif in the 3’ UTR (D3U-box) is critical for transcript stability of dmrt1 mRNAs from medaka and other vertebrates. The goal of this project was to identify the proteins that interact with the D3U-box and to elucidate the molecular mechanism. Main results. We show here that in medaka two RNA-binding proteins with antagonizing properties competitively target this D3U-box, promoting either RNA stabilization in germ cells or degradation in the soma. One protein is the CUG binding protein (CUG-BP), which was shown to bind to mRNAs, and mediates rapid deadenylation, thus promoting mRNA degradation. The second protein that can bind to the D3U-box is the bicoid stability factor (BSF) that has initially been shown to be involved in increasing the stability of bicoid transcripts in Drosophila. With respect to the mechanism of action we could show that both proteins compete for the binding motif of the D3U-box. We also demonstrated that depending on the stoichiometry of both proteins, the half-life of the targeted mRNA is determined and modulated. Interestingly, the D3U-box is also conserved in other germ-cell transcripts, making them responsive to the same RNA binding proteins. Future prospects. The evolutionary conservation of the D3U-box motif within dmrt1 genes and other germ cell transcripts, together with preserved expression patterns of the targeting RNA binding proteins BSF and CUP-BP in subsets of germ cells, suggest this new mechanism for controlling RNA stability is not restricted to fishes, but might also apply to other vertebrates.
Projektbezogene Publikationen (Auswahl)
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(2015) Defective autophagy through epg5 mutation results in germ plasm and mitochondria reduction failure during spermatogenesis, FASEB J. 29(10)4145-61
Herpin, A., Englberger, E., Zehner, M., Wacker, R., Gessler, M. and Schartl, M.
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(2015) Plasticity of the gene regulatory networks controlling sex determination: of masters, slaves, usual suspects, newcomers and usurpators, EMBO reports. 16(10):1260-74
Herpin, A., Schartl, M.
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(2016) Retinoic acid and meiosis induction in adult versus embryonic gonads of medaka. Sci Rep 6, 34281
Adolfi, M.C., Herpin, A., Regensburger, M., Sacquegno, J., Waxman, J.S., and Schartl, M.
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(2018) Sox5 is involved in germ cell regulation and sex determination in medaka following co-option of nested transposable elements, BMC Biology 16(1):16
Schartl, M., Schories, S., Wakamatsu, Y., Nagao, Y., Hashimoto, H., Bertin, C., Mourot, B., Schmidt, C., Wilhelm, D., Centanin, L., Guiguen, Y. and Herpin, A.
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(2018) The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway, PNAS 115(50):12781-12786
Bertho, S., Herpin, A., Jouanno, E., Yano, A., Nicol, B., Müller, T., Pannetier, M., Pailhoux, E., Miwa, M., Yoshizaki, G., Schartl, M. and Guiguen, Y.
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(2019) A novel evolutionary conserved mechanism of RNA stability regulates synexpression of primordial germ cell-specific genes prior to the sex-determination stage in medaka, PLoS Biology 17(4):e3000185
Herpin, A., Schmidt, C., Kneitz, S., Gobé, C., Regensburger, M., Le Cam, A., Montfort, J., Adolfi, M.C., Lillesaar, C., Wilhelm, D., Kraeussling, M., Mourot, B., Porcon, B., Pannetier, M., Pailhoux, E., Ettwiller, L., Dolle, D., Guiguen, Y. and Schartl, M.
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(2019) Increase of cortisol levels after temperature stress activates dmrt1a causing female-to-male sex reversal and reduced germ cell number in medaka, Molecular Reproduction and Development 86(10):1405-1417
Adolfi, M. C., Fisher, P., Herpin, A., Regensburger, M., Kikuchi, M., Tanaka, M. and Schartl, M.
