A key to male fertility

Until now, mutations of the LH hormone receptor were the only explanation known for sexual precocity in boys. A team at the Institute of Genetics and Molecular and Cellular Biology (IGBMC, CNRS / Inserm / Université Louis Pasteur de Strasbourg)), in collaboration with researchers at the University of Dallas and the University of Louvain, has just identified a key regulator of male fertility, the SHP protein, bringing to light the major role it plays in controlling the synthesis of testosterone and in differentiation of germ cells in mouse testes. This work, published in the journal Genes & Development, suggests that it is worth exploring the signalling pathways controlled by SHP in men suffering from fertility disorders.

Puberty is the result of endocrine alterations programmed from the moment of sexual differentiation in the embryo and fœtus. It is characterized by anatomical alterations: the maturation of primary sexual characteristics (penis, scrotum and testes) and the appearance of secondary sexual characteristics (hair growth, breaking of the voice, growth, etc). Such changes are caused by processes within the brain, and in particular by a neuroendocrine gland, the pituitary gland, which secretes two hormones, FSH and LH. Both these hormones act on the testes, causing the production of sperm as well as the secretion of testosterone. Testosterone in particular is responsible for the development of secondary sexual characteristics in boys. At the current time, mutations of the LH receptor are the only known causes of sexual precocity in boys, which shows the important role that this signaling pathway plays in the control of the endocrine system.

At the Institute of Genetics and Molecular and Cellular Biology, a new player which is involved in the sexual maturation of male mice, the SHP protein, has been identified. The team led by Johan Auwerx decided to study the role of this protein in order to obtain a better understanding of the triggering of testosterone synthesis in the testes.

Two models of mouse were used, those which had SHP protein and those that did not. The result was astonishing. The mice without SHP were able to reproduce about a week earlier than the controls. This is a considerable difference since, as a general rule, male mice are sexually mature at 7 or 8 weeks. In addition, regardless of increased activity in the pituitary gland, mice without SHP produce more testosterone prematurely, leading to premature maturation of primary sexual characteristics. At the same time, the SHP protein controls the timing of the differentiation of the germ cells by inhibiting the metabolism of retinoic acids (see illustration). It should therefore be possible to look for mutations of SHP in order to improve our understanding of certain kinds of sexual precocity whose causes are as yet unexplained. It should also be pointed out that, because of the family that it belongs to, SHP is a potential therapeutic target, thanks to the development of new synthetic ligands. This work therefore opens up new prospects for research aimed at improving the production of sperm in men suffering from fertility disorders.

Further research is vital if we are to understand the overall mechanisms involved in sexual maturation in boys. However, these findings mean that we can now identify a new player involved in the control of male fertility.


###
Two microphotographs of a 28-day-old testis. Mice with the SHP protein show no differentiated germ cells (left), whereas mice with no SHP protein already have differentiated germ cells (shown by the arrows in the image on the right and recognizable by their spindle shape) which will give rise to sperm. © David Volle / CNRS 2007 (this image can be obtained from the CNRS photo library (photothèque du CNRS, 2007 01 45 07 57, 90, phototheque@cnrs-bellevue.fr)

REFERENCES

The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice. David H. Volle, Rajesha Duggavathi, Benjamin C. Magnier, Sander M. Houten, Carolyn L. Cummins, Jean-Marc A. Lobaccaro, Guido Verhoeven, Kristina Schoonjans & Johan Auwerx. Genes & Development (February 2007)