UC San Diego

Kisspeptin, encoded by the Kiss1 gene, is required for reproductive function. There are several distinct Kiss1 populations in the brain, and how these kisspeptin neurons are regulated is still not fully understood. The two largest hypothalamic Kiss1 populations reside in the ARC and AVPV and respond to sex steroids in opposing manners, one being negatively regulated and the other being positively regulated, respectively. As a result, in research experiments it has been technically difficult to visualize Kiss1 expression of both populations in the same animal. Here, we sought to establish a dose of estradiol (E2) for which both ARC and AVPV kisspeptin populations can be visualized with in situ hybridization. Using this E2 treatment in conjunction with the inducible diphtheria toxin receptor mouse line, we next aimed to exploit the different developmental ontogenies of the Kiss1 populations to selectively remove only the ARC Kiss1 neurons, which have been implicated in the maintenance of the reproductive axis. We discovered that administration of diphtheria toxin (DT) during early juvenile stage to transgenic mice with selective sensitivity to DT led to specific ablation of ARC Kiss1 neurons. Finally, to address lesser understood Kiss1 populations outside the hypothalamus, we used two transgenic mouse models lacking either ERα or ERβ and found that E2 positively regulates Kiss1 cells in the lateral septum (LS) via ERα. Understanding the role of the ARC and LS Kiss1 neurons may lead to a better understanding of how the reproductive axis is regulated and provide potential therapeutics for reproductive disorders.