Periodic Reporting for period 1 - RegADyn (In vivo characterization of novel actin dynamic regulators during cell migration)
Reporting period: 2020-06-01 to 2023-05-31
The overall scientifc goal of the Regadyn project carried out by the fellow Sophie Escot is to better understand the molecular machinery that control the ability of cells to migrate. Cell migration is a critical process for embryogenesis, defective migration being the basis of numerous developmental disorders. During adult life, migration is key to immune cell function and wound healing. Furthermore, acquisition of migratory properties by tumour cells triggers the formation of metastases, which is the most dreadful event during cancer progression.
To migrate, most cells rely on an internal skeleton (termed cytoskeleton), and mostly on one of its constituents, actin, which can be rapidly remodeled, to deform the cell, and allow it to move. Controlling the dynamics of actin is thus key in controlling cell migration. While the major molecular pathway controlling actin dynamics has been identified, it is now clear that this pathway is precisely fine-tuned, with many intricated feedback loops defining its properties. These feedback loops, by controlling actin dynamics in term control the speed of cell migration, but maybe more importantly, its directionality (the ability of cells to turn). The aim of the project was to characterize the in vivo function of the three candidate genes we had identified as potentially involved in these feedback loops. This in vivo characterization was performed in early zebrafish embryos, as it is close enough to human for the mechanisms to be conserved, it allows direct observation of cell migration in the intact living embryo, it allows easy genetic manipulations.
The Regadyn project is Career Restart project. Scientific knowledge is both complex and fast evolving. While it may take years for a researcher to acquire the knowledge, skills and technical tools to be able to produce original results, a one-year hiatus may be enough to be largely overtaken by the competition. This inability to stop for a while is a major handicap in building a career, especially for women who wish to have children. The aim of this project was to allow me to restart an academic career after a 15-month break to raise my child.
To migrate, most cells rely on an internal skeleton (termed cytoskeleton), and mostly on one of its constituents, actin, which can be rapidly remodeled, to deform the cell, and allow it to move. Controlling the dynamics of actin is thus key in controlling cell migration. While the major molecular pathway controlling actin dynamics has been identified, it is now clear that this pathway is precisely fine-tuned, with many intricated feedback loops defining its properties. These feedback loops, by controlling actin dynamics in term control the speed of cell migration, but maybe more importantly, its directionality (the ability of cells to turn). The aim of the project was to characterize the in vivo function of the three candidate genes we had identified as potentially involved in these feedback loops. This in vivo characterization was performed in early zebrafish embryos, as it is close enough to human for the mechanisms to be conserved, it allows direct observation of cell migration in the intact living embryo, it allows easy genetic manipulations.
The Regadyn project is Career Restart project. Scientific knowledge is both complex and fast evolving. While it may take years for a researcher to acquire the knowledge, skills and technical tools to be able to produce original results, a one-year hiatus may be enough to be largely overtaken by the competition. This inability to stop for a while is a major handicap in building a career, especially for women who wish to have children. The aim of this project was to allow me to restart an academic career after a 15-month break to raise my child.
The project had tree scientific aims: i. to test the in vivo function of the three candidate genes, and in particular, their potential involvement in cell migration; ii. for those actually controlling cell migration, unravel their direct effect on actin dynamics as well as their subcellular localization; iii. for those controlling cell migration, position them in feedback loops. The first two aims were achieved, with in particular, one gene, named nhsl1b, that appeared to control the migration of some important progenitor cells in the early embryo. I could show that is does so regulating the length and lifetime of actin-rich extensions used by cells to migrate. Aim 3 ran into technical and Covid induced difficulties. However, while facing these difficulties, I uncovered an unexpected role of an actin regulator in controlling the formation of cilia (small motile extensions produced by some cells, and essential to the function of many organs, including kydneys or inner-ear). I therefore decided to fully characterize this exciting new function, in a collaboration with a lab at the Pasteur Institute.
These scientific results have been disseminated through my participation to 4 conferences, and through the publication of 4 articles. They were also shared with a wider audience, through a booth at the “fête de la science” (science fair), and by hosting in the lab middle and high school students.
To allow a career restart, the project has enabled me to broaden my areas of expertise. In particular, I received formal and practical training in the use of the zebrafish as a model system, as well as acquired key skills in cell migration analysis. As the host laboratory is highly interdisciplinary, I directly benefited from the interaction with my physicist colleagues, and acquired strong knowledge and know-how in cutting-edge microscopy techniques, including confocal, two-photon and light sheet microscopy. Conversely, I was able to transfer my expertise in developmental biology to some of my colleagues’ the research projects and develop fruitful collaborations.
The project gave me the opportunity to teach 100 hours, gaining crucial experience for my applications to academic positions. I was in charge on the scientific and financial management of the project, and supervised students and a technician, therefore preparing myself for the role of a principal investigator.
These scientific results have been disseminated through my participation to 4 conferences, and through the publication of 4 articles. They were also shared with a wider audience, through a booth at the “fête de la science” (science fair), and by hosting in the lab middle and high school students.
To allow a career restart, the project has enabled me to broaden my areas of expertise. In particular, I received formal and practical training in the use of the zebrafish as a model system, as well as acquired key skills in cell migration analysis. As the host laboratory is highly interdisciplinary, I directly benefited from the interaction with my physicist colleagues, and acquired strong knowledge and know-how in cutting-edge microscopy techniques, including confocal, two-photon and light sheet microscopy. Conversely, I was able to transfer my expertise in developmental biology to some of my colleagues’ the research projects and develop fruitful collaborations.
The project gave me the opportunity to teach 100 hours, gaining crucial experience for my applications to academic positions. I was in charge on the scientific and financial management of the project, and supervised students and a technician, therefore preparing myself for the role of a principal investigator.
The Regadyn project has provided new knowledge on the genes controlling cell migration, improving our understanding of this mechanism and identifying potential therapeutic targets to limit migration (to prevent metastasis), enhance migration (to favor wound healing) and control migration (to build in vitro tissues for regenerative medicine). During the project, I also produced original results regarding ciliogenesis, the defects of which are associated with numerous pathologies. The project allowed knowledge transfer between me and my host institution, from which both benefited, and gave my training, networking and teaching opportunities.
In conclusion, the Regadyn project achieved most of its objectives, providing new insights into the molecular machinery that controls cell migration, and put me in a good position to obtain an academic position.
In conclusion, the Regadyn project achieved most of its objectives, providing new insights into the molecular machinery that controls cell migration, and put me in a good position to obtain an academic position.