Project description
Investigating the genetic routes of sex determination
In many mammalian species sex is determined genetically by the expression of one or several genes carried by sex chromosomes. There is an antagonism between male and female pathways in fate reinforcement, yet the mechanism of interplay and downstream events remain elusive. The EU-funded EnhanceSex project has developed an in vitro and in vivo system for generating mouse gonadal progenitors from embryonic stem cells and will use it to study the gene regulatory networks governing mammalian sex determination. Apart from fundamental knowledge into development, project results will provide important insight into disorders of sex development and open new possibilities for novel interventions against infertility.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- engineering and technology electrical engineering, electronic engineering, information engineering electrical engineering power engineering electric power generation combined heat and power
- natural sciences biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2021-STG
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52900 Ramat Gan
Israel
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