Sex determination and testis development

Our long-standing interest lies in the elucidation of the molecular mechanisms regulating gonadal differentiation and testicular function. We use molecular, cellular, and mouse functional genomics to investigate the complex gene networks that regulate primary sex determination, testis development, and functions.

More precisely, we are investigating the following topics:

 

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Understanding how distinct cell populations diverge from multipotent progenitors is a major goal in dev
elopmental biology. The adrenal gland and the gonads represent the two major steroidogenic organs in mammals and are absolutely central to the regulation of body homeostasis, metabolism, sexual development, and reproduction. Both organs share a common developmental origin, the adrenogonadal primordium (AGP), composed of a population of uncharacterized SF1+ progenitor cells.  AGP specification and differentiation into testis or ovaries, and adrenal glands represents a unique model system for studying cell fate decisions during mammalian organ development. While major outstanding questions regarding the identity of these progenitors and the transcriptional events that drive cell lineage specification remain, traditional experimental approaches, such as genome-wide transcription analysis, are rendered completely ineffective by the very small number of progenitor cells.

Here, we build on our previous achievements and combine single-cell RNA sequencing and mouse lineage tracing experiments to investigate how cell-fate decisions are made during testicular, ovarian, and adrenal development. We plan to identify progenitor cells, map lineage progression, and cell type diversification, and reconstruct the genetic programs controlling their differentiation into testicular, ovarian, and adrenocortical cells.

 

Model of steroidogenic Lineage specification during male sex determination (Ademi et al Cell Rep. 2022)

This project should provide a comprehensive transcriptional blueprint outlining steroidogenic organ specification and differentiation. These results should have also broad physiological and clinical applications, contributing to a detailed understanding of both normal physiology and development, and impairment and disturbances in sexual development, fertility, and endocrinology.

 

Recently published examples

  • Ademi H,  Djari C, Mayère C, Neirijnck Y, Sararols P, Rands CM, Stévant I, Conne B,  Nef S: Deciphering the origins and fates of steroidogenic lineages in the mouse testis. Cell Reports. in press. 
  • Chloé Mayère  C, Regard V, Perea-Gomez A, Bunce C, Neirijnck Y, Djari C, Sararols P, Reeves R, Greenaway S, Simon M, Siggers P, Condrea D, Kühne F, Stévant I, Gantar I, Batti L, Ghyselinck NB, Wilhelm D, Greenfield A, Capel B, Chaboissier MC, Nef S: Origin, specification and differentiation of a rare supporting-like lineage in the developing mouse gonad. Science Advances. in press.
  • Sararols P, Stévant I, Neirijnck Y, Rebourcet D, Darbey A, Curley MK, Kühne F, Dermitzakis E, Smith LB, Nef S: Specific transcriptomic signatures and dual regulation of steroidogenesis between fetal and adult mouse Leydig cells. Front Cell Dev Biol. 2021 Jun 28;9:695546. doi: 10.3389/fcell.2021.695546. eCollection 2021. Pubmed
  • Mayère C, Neirijnck Y, Sararols P, Rands CM, Stévant I, Kühne F, Chassot AA, Chaboissier MC, Dermitzakis ET, Nef S: Single- cell transcriptomics reveal temporal dynamics of critical regulators of germ cell fate during mouse sex determination. FASEB J. 2021 Apr;35(4):e21452. doi: 10.1096/fj.202002420R. Pubmed

 

DSD

Congenital defects such as disorders of sexual differentiation (DSD) are rare diseases that present considerable challenges for physicians, parents and affected individuals. Unfortunately a large fraction of human cases of DSD are unexplained, clearly indicating that a significant number of genes (or regulatory regions of known genes) involved in sex determination remain to be identified. There are two classical and complementary ways to identify and characterize the function of genes involved in the process of sex determination: the first relies on in vivo gain- and loss-of-function experiments in mice. In fact, mouse functional genomics has remained over the years the gold standard for candidate gene validation/characterization. In parallel, the identification of novel pathogenic mutations in affected patients with unresolved cases of DSD has also been a successful approach to identify new genes involved in testicular or ovarian differentiation processes.

We are using cutting-edge techniques in human and mouse genetics, to investigate the complex mechanisms of gonadal differentiation. Our first axis of research relies on human genetics: we apply genetic tools such as CGH arrays and exome sequencing to a cohort of unresolved cases of patients suffering from 46,XY DSD, 46 XY complete gonadal dysgenesis (CGD) and 46,XX DSD to reveal new genes and pathways involved in gonadal development. As a second step, we use mouse functional genetics to validate and characterize the function of candidate genes involved in the process of sex determination