Molecular and Developmental biology of sexual development
Serge NEF
Research:
Testicular development and spermatogenesis
Thematics:
- Developmental genetics
- Sex determination and gene regulation
- Mechanisms of Endocrine Disruption on sexual development and metabolism
- Role of miRNA on spermatogenesis
Objectives
Our long-standing interest lies in the elucidation of the molecular mechanisms regulating gonadal differentiation and testicular function. In particular, we are investigating:
1) The roles of microRNAs in testicular development and function
Recently, a novel mechanism of post transcriptional regulation mediated by microRNA has emerged. MicroRNAs are non-protein-coding small RNAs that act by negatively regulating gene expression at the post-transcriptional level either by degrading target mRNA or by inhibiting translation. Specific lines of genetically modified mice provide platforms to study aspects of testicular differentiation and function. Our data provide in vivo evidence that Dicer, a RNAseIII-related enzyme responsible for processing miRNAs to the mature form, and by inference miRNAs are essential for normal spermatogenesis. Specific ablation of Dicer, either in the germ cell lineage or in Sertoli cells, leads to infertility due to the incapacity of mutant mouse testes to complete spermatogenesis. We are also in the process of identifying which miRNAs expressed in Sertoli cells and/or germ cells are important for spermatogenesis and what are their relevant target genes.
2) The role of insulin signaling in regulating testicular function
The insulin family of growth factor including insulin, Igf1 and Igf2 is essential for male reproductive function and spermatogenesis. Studying the function of these growth factors by constitutive invalidation of their cognate receptor is difficult due to perinatal lethality. We are currently developing a line of research aimed at identifying the function of the insulin signaling in each relevant cell lineage of the testis using the Cre/lox technology. So far, our results suggest that both Ir and Igf1r are important for Sertoli cell survival, morphology and function.
3) Mechanisms of endocrine disruption on testicular development and metabolism
Many industrial and environmental chemicals mimic, antagonize or indirectly affect the activity of steroid hormones. These compounds are known as endocrine disruptors. The development of the male urogenital system in mammals is affected by exposure to endocrine disruptors and in particular xeno-estrogens. The aim of our project is to investigate the mechanisms by which endocrine disruptors such as diethylstilbestrol (DES) affect the endocrine function of the testis, cause urogenital malformations and decrease reproductive health. In particular, we study the molecular mechanisms mediating the inhibitory actions of xeno-estrogens on fetal Leydig cells, with an emphasis on steroidogenesis and Insl3 gene expression.
Similarly, endocrine disruptors with estrogenic activities may also affect glucose and lipid metabolism. We recently developed a project aimed at investigating and understanding the molecular mechanisms by which natural phytoestrogens, in particular dietary isoflavones, modulate glucose metabolism and fat deposition.
