Abstract
Conception rates among dairy cows in Japan have declined in recent decades. To enhance our understanding of the genes involved in conception rates, we conducted a genome-wide association study (GWAS) using 822 Holsteins and identified a single-nucleotide polymorphism (SNP) associated with conception rate: A+169G in the 3’ untranslated region (UTR) of unc-5 homolog C (UNC5C). Cows with higher conception rates carried the A polymorphism in the UNC5C 3’UTR. Luciferase assays and quantitative analysis of allele ratios revealed that UNC5C transcripts with the A polymorphism were expressed at higher levels than those carrying the G polymorphism. UNC5C transmits either pro- or anti-apoptotic signals depending on the availability of its ligand, Netrin-1. UNC5C expression is negatively regulated by reproductive homeobox X-linked 5 (Rhox5), and the Rhox5 locus is methylated by G9a methyltransferase. G9a-knockout mice have previously been demonstrated to be subfertile, and we found that UNC5C, G9a, and Netrin-1 expression levels increased from the 4-cell stage to the blastocyst stage in fertilized murine embryos, whereas Rhox5 expression decreased. Repression of UNC5C, G9a, or Netrin-1 or forced expression of Rhox5 in the anterior nucleus stage inhibited development to the blastocyst stage, suggesting that cows carrying the G polymorphism in UNC5C might have lower conception rates because of the poor development of preimplantation embryos. This study provides novel insights into the role of UNC5C during embryonic development.
Highlights
Conception rates have decreased dramatically over recent decades in Japanese dairy industry
unc-5 homolog C (UNC5C) has been well studied in the brain, its expression has recently been determined to be controlled by reproductive homeobox X-linked 5 (Rhox5) in Sertoli cells in the testis, and UNC5C mutant mice have been shown to possess decreased male germ cell apoptosis [15], suggesting that the protein functions in the reproductive tract
We found that UNC5C, Rhox5, and G9a were selectively expressed during embryonic development
Summary
Conception rates have decreased dramatically over recent decades in Japanese dairy industry. We report a new gene, unc-5 homolog C (UNC5C), which is associated with conception rate in the Holstein cattle population. UNC5C has been well studied in the brain, its expression has recently been determined to be controlled by reproductive homeobox X-linked 5 (Rhox5) in Sertoli cells in the testis, and UNC5C mutant mice have been shown to possess decreased male germ cell apoptosis [15], suggesting that the protein functions in the reproductive tract. Because Rhox has been detected in the ovary [17], it is possible that UNC5C may function in the female reproductive tract under the control of Rhox. G9a-knockout female mice are subfertile [20] These results imply that the G9a-Rhox5-UNC5C pathway might be important for female fertility. We report that UNC5C is a novel locus associated with conception rate in Holsteins. Our work has revealed an unexpected role of UNC5C in the female reproductive system
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