Genetically modified mouse models for the analysis of reproductive disorders
William Colledge & Xavier dAnglemont de Tassigny
The mammalian reproductive axis is activated at puberty by neuroendocrine events within the hypothalamus that initiate the pulsatile secretion of GnRH. GnRH acts on the anterior pituitary to stimulate production of the gonadotrophic hormones (LH and FSH) which bring about maturation of the gonads. Both naturally occuring and genetically modified mutant mice have provided insights into the molecular events that maintain the function of each part of this reproductive axis. The crucial role that GnRH plays in activating the reproductive axis is illustrated by the sterility of mutant mice that cannot synthesize GnRH. Transgenic mice have also led to the identification of two key proteins that are important regulators of GnRH release; these are the G-protein coupled receptor, GPR54, and its ligands (kisspeptins) encoded by the Kiss1 gene. Kisspeptins are expressed by neurons in the AVPV and the ARC regions of the hypothalamus while Gpr54 is expressed by GnRH neurons. Kisspeptin expression is differentially regulated by gonadal steroids which provides a mechanism by which sex steroids can regulate GnRH release under different physiological conditions. Gpr54 and Kiss1 mutant mice are sterile, hypogonadal and have very low gonadotrophic and sex steroid hormone levels. Spermatogenesis and ovulation are severely impaired and mutant females do not show estrous cycling. The Gpr54 and Kiss1 mutant mice cannot produce the pre-ovulatory LH surge after appropriate hormonal stimulation and cannot activate kisspeptin or GnRH neurons as judged by c-fos induction. Recently, injection of kisspeptin antagonists into the ARC has been shown to inhibit pulsatile LH release. Thus, kisspeptin signalling in the hypothalamus is required for activation of the reproductive axis at puberty, to generate the pre-ovulatory LH surge and to maintain tonic GnRH/LH pulsatility.