Project description
Flies may provide clues to the role of sex chromosomes in disease dimorphism
All cells in an organism have all the organism’s chromosomes and the ability to make all the proteins the organism needs. Even somatic cells such as those in the kidneys or intestines have the sex chromosomes. Each cell expresses only the genes it needs to do its job, and sex-organ cells do that in a way that modulates hormones related to sex differences. However, it is not clear how sex chromosomes in other cells affect sexual dimorphism and how this relates to disease. CellSex plans to find out via a comprehensive body-wide study of the Drosophila fly model. Pioneering organ-specific Y-chromosome deletion studies should provide answers to long-open questions about cellular sex and disease.
Objective
The difference between males and females constitutes the largest phenotypic dimorphism in most species. In humans, this variation accounts for differences seen in the risk, incidence and response to treatment for a plethora of diseases; and much of these striking differences are not explained at this time. While sex organ-derived hormones play key roles in sculpting and maintaining sex differences, my recent work highlighted the importance of cell-intrinsic mechanisms involving the sex chromosomes. In fact, using fly models I demonstrated that the sex of intestinal stem cells plays a key role in the adult gut, both for the organ size and for the sex-specific pre-disposition to tumours. While these findings establish the proof-of-principle of the influence of sex chromosomes in adult cells, essential gaps remain to be filled. Indeed, the full range of phenotypic consequences of the presence of sex chromosomes in somatic cells, the genes, the mechanisms involved and their sites of action remain entirely elusive. My research proposal aims to understand how cellular sex impacts physiology across the body using Drosophila as an in vivo model. This question has been poorly investigated in part due to the difficulties of studying sex chromosome effects. Flies will offer the remarkable possibility of generating mosaic animals in which sex chromosomes will be genetically manipulated in defined organs.
Here I will combine classical fly genetics, novel genetic methods and cutting-edge genomic techniques to: 1. characterise new cellular sex pathways driving sex differences in body size and in behaviours, 2. study the role of sex determinant coding changes in sex trait evolution, 3. achieve, for the first time, organ-specific Y chromosome deletion, and use this new method to study how the Y chromosome controls sex gap in longevity.
Thus, results from this research should have major impact on our understanding of the importance of cellular sex in physiology and disease.
Fields of science
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Funding Scheme
ERC-STG - Starting GrantHost institution
75794 Paris
France