Abstract
Congenital reproductive tract anomalies could impair fertility. Female and male reproductive tracts are developed from Müllerian ducts and Wolffian ducts, respectively, involving initiation, elongation and differentiation. Genetic basis solely for distal reproductive tract development is largely unknown. Lhfpl2 (lipoma HMGIC fusion partner-like 2) encodes a tetra-transmembrane protein with unknown functions. It is expressed in follicle cells of ovary and epithelial cells of reproductive tracts. A spontaneous point mutation of Lhfpl2 (LHFPL2G102E) leads to infertility in 100% female mice, which have normal ovarian development, ovulation, uterine development, and uterine response to exogenous estrogen stimulation, but abnormal upper longitudinal vaginal septum and lower vaginal agenesis. Infertility is also observed in ~70% mutant males, which have normal mating behavior and sperm counts, but abnormal distal vas deferens convolution resulting in complete and incomplete blockage of reproductive tract in infertile and fertile males, respectively. On embryonic day 15.5, mutant Müllerian ducts and Wolffian ducts have elongated but their duct tips are enlarged and fail to merge with the urogenital sinus. These findings provide a novel function of LHFPL2 and a novel genetic basis for distal reproductive tract development; they also emphasize the importance of an additional merging phase for proper reproductive tract development.
Highlights
The reproductive tract is essential for successful reproduction in mammals
LHFPL2 belongs to the lipoma HMGIC fusion partner (LHFP) gene family, which includes six members, LHFP and LHFPL1-LHFPL5 that are predicted to be four transmembrane
Based on the full-length Lhfpl[2] transcript (Lhfpl2-001), the Lhfpl[2] mutant mice (MUT/ LHFPL2G102E) used in this study have a spontaneous mutation in the 676th nucleotide from G to A, resulting in a missense mutation of the 102nd amino acid from nonpolar glycine (G) to negatively charged glutamic acid (E) located on the predicated second transmembrane domain
Summary
The reproductive tract is essential for successful reproduction in mammals. The female reproductive tract, which includes oviduct, uterus, cervix, and vagina, coordinately provides suitable environments in different parts of the tract for mating, fertilization, embryo transport, embryo implantation, embryo development, and fetus delivery. In female embryo, the WD degenerates and the MD differentiates into morphologically and functionally different subsections of the reproductive tract, i.e. oviduct, uterus, cervix, and upper vagina, which will extend to form the lower vagina during postnatal development[4,8,9]; while in male embryo, the MD degenerates and the WD differentiates into epididymis, vas deferens, seminal vesicle, and ejaculatory duct[4]. It was our initial intention to use this Lhfpl[2] mutant as a loss-of-function model for studying mechanisms of vaginal opening, which are not well understood. Our study led us away from the initial intention and to the novel findings that LHFPL2 is essential for distal reproductive tract development in both female and male mice
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