Projektbeschreibung
Genetische Signalwege der Geschlechtsdetermination
Bei vielen Säugetierarten wird das Geschlecht durch Expression eines oder mehrerer Gene determiniert, die sich auf den Geschlechtschromosomen befinden. Dass zwischen männlichen und weiblichen Signalwegen für Geschlechtsdetermination ein Antagonismus besteht, ist bereits klar, nicht jedoch, welche nachgelagerten Ereignisse dabei stattfinden. Das EU-finanzierte Projekt EnhanceSex entwickelte ein In-vitro- und In-vivo-System, um aus embryonalen Stammzellen von Mäusen Gonadenvorläufer zu generieren. Nun werden daran genregulatorische Netzwerke untersucht, die bei Säugetieren die Geschlechtsdetermination steuern. Neben entwicklungsbiologischem Grundlagenwissen soll dies wichtige Einblicke zu Störungen der Geschlechtsentwicklung liefern und neue Behandlungsmöglichkeiten bei Unfruchtbarkeit eröffnen.
Ziel
During mammalian sex determination, the bipotential embryonic gonad adopts either testicular or ovarian cell fates. This process highly relies on precise expression of several pro-male versus pro-female factors, most of which are transcription factors (TFs) and signalling pathway components. Yet, we still do not understand the interplay and hierarchy among these factors, their direct target genes, the regulatory elements they bind to, nor do we have an in vitro system to address these questions.
We recently explored the complex gene expression regulation of Sox9, a key pro-male factor, and identified several active testis-specific enhancers. Remarkably, deletion of one of these led to XY male-to-female sex reversal in mice. The presence of several functional enhancers highlights the complex gene expression regulation present during sex determination, which we aim to address here in a systematic manner. Furthermore, we recently developed a system to generate mouse and human gonadal progenitors from embryonic stem cells. Building on our exciting results, we seek to decipher the gene regulatory networks governing mammalian sex determination using in vivo and in vitro approaches. This proposal will pursue three complementary aims: (i) Identify target genes of the key factors controlling gonad formation; (ii) Map the regulatory elements bound by these factors; (iii) Develop an in vitro organoid system to model testis development. Using cutting edge techniques as CUT&RUN ChIP-Seq, ATAC-Seq, Promoter Capture Hi-C, CRISPR genome editing, organoid culture and 3D scaffolding development, we will address the complex gene expression regulation governing sex determination. Insights gained from this basic research will shed light on cell fate decisions in general, allow better diagnosis of many patients with Disorders of Sex Development, and offer an in vitro system to study gonad development and function with implications for understanding and treating infertility.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
52900 Ramat Gan
Israel