Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice.
The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43-52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.
Lapatto
Risto
R
Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. rlapatto@partners.org
Pallais
J Carl
JC
Zhang
Dongsheng
D
Chan
Yee-Ming
YM
Mahan
Amy
A
Cerrato
Felecia
F
Le
Wei Wei
WW
Hoffman
Gloria E
GE
Seminara
Stephanie B
SB
D000818:Animals; D005260:Female; D006062:Gonadotropins / Q000097:blood; D007006:Hypogonadism / Q000150:complications / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D007246:Infertility / Q000209:etiology; D047908:Intracellular Signaling Peptides and Proteins; D059648:Kisspeptins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010053:Ovary / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D000074502:Receptors, Kisspeptin-1; D012741:Sexual Maturation; D013094:Spermatozoa / Q000502:physiology; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000097:blood
D006062:Gonadotropins; D047908:Intracellular Signaling Peptides and Proteins; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D010446:Peptide Fragments; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C523970:metastin protein (43-52), mouse; D013739:Testosterone; D017346:Protein Serine-Threonine Kinases; C530659:Uhmk1 protein, mouse