Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 144

Mouse Models of Kiss1r Disruption
The phenotype of male and female mice with disruption of the Kiss1r gene is con-
sistent with that exhibited by patients carrying biallelic inactivating mutations in
KISS1R . Male and female mice with congenital disruption of the Kiss1r gene or the
gene encoding its ligand, Kiss1 , fail to undergo sexual maturation, have very small
gonads, low serum gonadotropins and sex steroid levels, and are infertile [ 9 , 21 - 23 ,
36 , 69 ]. These models provide evidence that the absence of expression of either
KISS1R or kisspeptin cannot be effectively compensated, which suggests a lack of
redundancy for at least some important biological effects of the kisspeptin/KISS1R
system on reproductive function and puberty [ 69 ]. Despite severe impairment of
spermatogenesis in males and of estrous cyclicity and ovulation in females, Kiss1r
null mice can respond to exogenous stimulation with GnRH (9), consistent with an
innate failure to secrete GnRH.
Interestingly, mice with disruption of the Kiss1r ligand, kisspeptin, exhibit a less
severe phenotype when compared to Kiss1r null mice; nevertheless, Kiss1 null mice
also have impaired spontaneous puberty and are infertile [ 23 , 24 ]. Males and
females null for Kiss1 have larger gonads and males have a less severe defect in
spermatogenesis when compared to Kiss1r null mice. Additionally, LH and FSH
responsiveness to kisspeptin is preserved in males and females null for Kiss1 .
Conversely, LH and FSH responsiveness to kisspeptin is lost in Kiss1r null males
and females, which emphasizes the requirement of Kiss1r expression for the effect
of kisspeptin on gonadotropin secretion [ 23 ]. Although males from both lineages
exhibited low basal testosterone, the decrease in Kiss1r null males was 87%,
whereas Kiss1 null males were less affected, exhibiting only a 41% decrease when
compared to the wild type basal testosterone levels. The response of testosterone to
stimulation was below normal in males from both lineages; however, the average
values reached in Kiss1 null males were over 12-fold higher than those reached in
Kiss1r null males [ 23 ].
Nonetheless, some phenotypic differences are noticeable among the reported
Kiss1r mutant lineages, which may be related to the gene disruption strategy used
in each case. The strategies used to disrupt Kiss1r in mice have been nicely sum-
marized in a review by Colledge [ 69 ] (also see Chap. 22 ) . Three of the Kiss1r null
lineages were generated by gene targeting and deletion of part of the coding
sequence of the Kiss1r gene [ 9 , 22 , 23 ]. The lineage generated by Paradigm
Therapeutics has a deletion of 702 base pairs, which includes 92 base pairs from
exon 1, the entire intron 1 and 101 base pairs of exon 2 [ 9 ]. The lineage generated
by Schering Plough is missing 52 base pairs within exon 2 of the Kiss1r coding
sequence [ 22 ]; the lineage generated by Harvard Reproductive Endocrine Sciences
Center has the entire exon 2 of the Kiss1r gene deleted from the sequence [ 23 ]. The
disruption of the Kiss1r gene in an additional lineage was created without deletions
in the coding sequence, by inserting a retrovirus within intron-2 of the Kiss1r gene
[ 21 , 36 ]. The insertion includes two polyadenylation sequences designed to termi-
nate transcription from the Kiss1r promoter, which should greatly impair Kiss1r