Effects of an Igf1 gene null mutation on mouse reproduction.

Abstract

Both sexes of adult mice homozygous for a targeted mutation of the Igf1 gene, encoding insulin-like growth factor 1, are infertile dwarfs (approximately 30% of normal size). The testes are reduced in size less than expected from the degree of dwarfism but sustain spermatogenesis only at 18% of the normal level. The epididymides are overall nearly allometric to the reduced body weight, but the distal regions of the duct, vas deferens, seminal vesicles, and prostate are vestigial. Despite the mutational impact on the epididymis, capacitated sperm are able to fertilize wild type eggs in vitro. It is hypothesized that the infertility of male mutants is caused by failure of androgenization resulting in absence of mating behavior, due to drastically reduced levels of serum testosterone (18% of normal). This hormonal deficiency was correlated with an ultrastructural analysis of mutant Leydig cells revealing a significant developmental delay, while assays in organ culture showed that the basal and LH-stimulated production of testosterone by testicular parenchyma is reduced in comparison with wild type controls. The female mutants fail to ovulate even after administration of gonadotropins, which is apparently the primary cause of their infertility, and possess an infantile uterus that exhibits a dramatic hypoplasia especially in the myometrium. The phenotypic manifestations of the mutation were correlated with the localization of transcripts for insulin-like growth factor I and its cognate receptor in wild type reproductive tissues by in situ hybridization.

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

“…The importance of IGF1 in uterine biology was shown by studies within IGF1-null mutant mice that were shown to have hypotrophic uteri with minimal development of the myometrium (20), which is consistent with studies showing that 125 I-IGF1 bound to cells in the myometrium (17). Similarly, using organ culture of immature uterus, IGF1 was shown to potentiate the proliferative response principally in the myometrium but also in the stroma (16).…”

In Vivo Regulation of CrkII and CrkL Proto-oncogenes in the Uterus by Insulin-like Growth Factor-I

“…In light of these data, we decided to examine whether IGF-IR activation in vivo regulates the phosphorylation of the Crk proteins and their interaction with paxillin, previously identified as having high affinity binding sites for the Crk SH2 domain (22,26). The development of the uterus is regulated by the IGF system acting in a paracrine manner, with uterine growth severely retarded in mice in which the Igf1 gene has been deleted by homologous recombination (19). IGF-IR mRNA is expressed at all stages of uterine development in both the myometrium and endometrium, while IGF-I mRNA exhibits a more restricted pattern of expression that is dependent on the stage of development (19).…”

“…The IGF-IR is known to have a critical role in mediating the effects of estrogen on the development of the uterus in the rodent. The development of the uterus is severely impaired in mice homozygous for a deletion of the IGF-I gene (19), while estrogen treatment of ovariectomized rats stimulates the tyrosine phosphorylation of the IGF-IR ␤-subunit and IRS-1 (20).…”

Emerging role of PLAG1 as a regulator of growth and reproduction

“…Like gonadotropins, GH is secreted by the anterior pituitary where Plag1 is expressed. In addition, GH has a direct effect on the IGF system that regulates reproductive physiology (Baker et al 1996, Zhou et al 1997, Hull & Harvey 2000, Pitetti et al 2013, Zhou et al 2013, Wolfe et al 2014 and that has been systematically identified as a target of Plag1. However, Plag1 KO mice do not seem to have a lower number of hypophyseal GH cells .…”