title: 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.
authors.affiliation: The Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Simina M
authors.initials: SM
authors.lastname: Popa
authors.forename: Ryutaro M
authors.initials: RM
authors.lastname: Moriyama
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Caligioni
authors.forename: Jasmine J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Cho
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Concepcion
authors.forename: Amy E
authors.initials: AE
authors.lastname: Oakley
authors.forename: In Hae
authors.initials: IH
authors.lastname: Lee
authors.forename: Elisenda
authors.initials: E
authors.lastname: Sanz
authors.forename: Paul S
authors.initials: PS
authors.lastname: Amieux
authors.forename: Alain
authors.initials: A
authors.lastname: Caraty
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: Victor M
authors.initials: VM
authors.lastname: Navarro
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Donald K
authors.initials: DK
authors.lastname: Clifton
authors.forename: Robert A
authors.initials: RA
authors.lastname: Steiner
mesh_terms: D000818:Animals; D004399:Dynorphins / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics; D018042:Receptors, Neurokinin-3 / Q000235:genetics; D012098:Reproduction / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D012737:Sex Factors; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015320:Tachykinins / Q000235:genetics
chemical_list: D059648:Kisspeptins; D011498:Protein Precursors; D018042:Receptors, Neurokinin-3; D015320:Tachykinins; C044206:preprotachykinin; D049452:Green Fluorescent Proteins; D004399:Dynorphins