Redundancy in Kiss1 Expression Safeguards Reproduction in the Mouse

Abstract

Kisspeptin (Kiss1) signaling to GnRH neurons is widely acknowledged to be a prerequisite for puberty and reproduction. Animals lacking functional genes for either kisspeptin or its receptor exhibit low gonadotropin secretion and infertility. Paradoxically, a recent study reported that genetic ablation of nearly all Kiss1-expressing neurons (Kiss1 neurons) does not impair reproduction, arguing that neither Kiss1 neurons nor their products are essential for sexual maturation. We posited that only minute quantities of kisspeptin are sufficient to support reproduction. If this were the case, animals having dramatically reduced Kiss1 expression might retain fertility, testifying to the redundancy of Kiss1 neurons and their products. To test this hypothesis and to determine whether males and females differ in the required amount of kisspeptin needed for reproduction, we used a mouse (Kiss1-CreGFP) that has a severe reduction in Kiss1 expression. Mice that are heterozygous and homozygous for this allele (Kiss1(Cre/+) and Kiss1(Cre/Cre)) have ∼50% and 95% reductions in Kiss1 transcript, respectively. We found that although male Kiss1(Cre/Cre) mice sire normal-sized litters, female Kiss1(Cre/Cre) mice exhibit significantly impaired fertility and ovulation. These observations suggest that males require only 5% of normal Kiss1 expression to be reproductively competent, whereas females require higher levels for reproductive success.

AgRP to Kiss1 neuron signaling links nutritional state and fertility

“…Cre:GFP , and Gnrh GFP have been characterized (24,46,47); Agrp Cre:GFP and Kiss1 Cre:GFP lines were backcrossed to C57BL/6 background more than six generations. We used a combination of male and female animals in this study.…”

Kisspeptin and energy balance in reproduction

“…So it is possible that the remaining (but severely limited) LepR expression on kisspeptin neurons following cre-lox recombination may still be adequate for the relay of leptin signaling to kisspeptin neurons and in-turn fertility. Of note here is the apparent redundancy in Kiss1 expression required for fertility in mice (Popa et al 2013). Equally, it is noted in Kiss1-Cre LepR flox/flox mice that LepR deletion was also apparent in the ovary and testes .…”

“…However, it is questionable whether a complete loss of kisspeptin cells was achieved. It is likely that this result reflects redundancy in kisspeptin neurons and signaling as genetically targeted mice with 50 and 95% reductions in Kiss1 transcript still maintain, albeit impaired in females, fertility (Popa et al 2013). In addition, the DBA/2J mouse strain possess less than one-tenth the level of Kiss1 mRNA in the brain than the C57BL/6 mice (Quennell et al 2011), yet are fertile.…”

Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

“…Because GnRH neurons become more responsive to the effects of kisspeptin over development (45), we suggest that the increase in Kiss1r-positive cilia per neuron may contribute to this process. Our results also show that ablation of cilia on GnRH neurons affects neither puberty nor adult reproductive function in mice; this is perhaps not surprising, because there is incredible redundancy in the Kiss1 signaling pathway in the brain, which supports reproductive function with only minute quantities of Kiss1 activity (46). In addition, there is evidence for Kiss1r signaling at the nerve terminals (47), which could overcome the loss of Kiss1r ciliary signaling.…”