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The MOSDER project (2022-2026, 433kE) is led by Frédéric Jean-Alphonse, in collaboration with the Institute of Functional Genomics of Montpellier.

Multi-dimensional organization of signaling dynamics encoded by gonadotropin receptors

Recent advances show that G protein-coupled receptor (GPCR) mediated signaling through G protein can be spatially and temporally regulated to achieve specific physiological responses1-3. Previous studies from partner 1 and collaborators indicate that both gonadotropin receptors, the follicle-stimulating hormone receptor (FSHR) and the luteinizing hormone receptor (LHR), activate Gs protein-mediated signaling from the cell surface and from several endocytic compartments. However, the role for FSHR and LHR-mediated Gs signaling from distinct cellular locations on gonadal physiology remains largely unexplored. We hypothesize that FSHR and LHR signal from distinct cellular compartments to specifically and precisely regulate distinct gonadal functions. Consequently, the objective of the “MOSDER” project is to gain comprehensive knowledge on how FSHR and LHR control reproduction through spatial and temporal organization of Gs protein-mediated signaling at the cellular level. Therefore, the project aims i) at determining the signaling dynamics generated from the plasma membrane and endosomes, ii) at deciphering the functional consequences of compartmentalized signaling, iii) at elucidating the molecular mechanisms of receptor trafficking and signaling in each signaling compartment and iv) at characterizing the functional selectivity properties (biased signaling) of new LHR and FSHR ligands to specifically modulate trafficking and signaling.

The OVOPAUSE project (2022-2027, 447kE) is led by Romain Yvinec, in collaboration with the Fish Physiology and Genomics Laboratory (INRAE ​​Rennes) and the Functional and Adaptive Biology Laboratory (Paris Diderot University, CNRS, INSERM).

Dynamics and control of female germ cell populations: understanding aging through population dynamics models

Reproductive function in females is dependent on a massive production of specialized germ cells, “oocytes”. In women, as in most mammal species, the stock of oocytes is established in the perinatal period and continues to decrease throughout life, leading to its depletion at menopause and the cessation of reproductive function. . Oocytes are surrounded by layers of somatic granulosa cells to form ovarian follicles. Different populations of follicles co-exist in the ovary: primordial, quiescent follicles, which constitute the stock of follicles available for reproduction, and growing follicles. Regularly and until exhausted, primordial follicles are recruited into the pool of growing follicles, according to a tightly regulated dynamic leading either to their final maturation for ovulation, or to their degeneration by a physiological process. Ovulation requires fine coordination between the recruitment of an adequate number of primordial follicles and the maturation of a sufficient number of follicles.

Accelerated depletion of primordial follicles is a cause of premature ovarian failure. Impaired follicular growth also leads to fertility disorders. Controlling the distribution of populations of primordial follicles and growing follicles, through the recruitment and maturation of follicles, is a crucial issue for fertility, which is currently at the heart of assisted reproductive technologies.

The objective of OVOPAUSE is to establish 1/to what extent primordial follicles and growing follicles establish a controlled dialogue, in particular via hormonal signals and growth factors to ensure ovulation throughout reproductive life ; 2/ to quantify the dynamics and non-linear interactions involved within these populations of follicles; 3/ to monitor the depletion of the germ cell stock with age, whether before puberty or during reproductive life.

Follicle population distribution will be determined using innovative imaging approaches and artificial intelligence-based analyses, at different ages and stages of reproductive life in mice and medaka fish, two models animals relevant to reproductive biology. These models will allow us to carry out analyzes in a physiological context and, after manipulation, in a context where inter-follicular dialogue is disrupted. Using population dynamics models, we will build an integrative modeling framework to formulate and study the role of regulations on follicle dynamics. We intend to faithfully reproduce the size distribution and maturation of follicles, in a quantitative and dynamic manner. Statistical estimation procedures will reveal the regulations underlying follicle population management throughout reproductive life. An in-depth study of the sensitivity of the parameters will allow us to propose potential levers of action on the management of the ovarian reserve. We will study in particular scenarios for preserving the stock of ovarian follicles, of crucial importance in oncofertility, or the excess of growing follicles encountered in polycystic ovary syndrome.