BMP15 regulates the inhibin/activin system independently of ovulation rate control in sheep

Abstract

Polymorphisms in the gene encoding bone morphogenetic protein 15 (BMP15) have been associated with multiple ovulations in sheep. As BMP15 regulates inhibin expression in rodents, we assumed that the ovarian inhibin/activin system could mediate part of the effect of BMP15 mutations in the regulation of ovulation rate in sheep. To answer this question, we have studied the effects of two natural loss-of-function mutations of BMP15 on the expression of components of this system. The FecX and the FecX mutations, when present respectively in Rasa Aragonesa ewes at the heterozygous state and in Grivette ewes at the homozygous state, were associated with a twofold increase in ovulation rate. There were only small differences between mutant and wild-type ewes for mRNA expression of INHA, INHBA, ACVR1B, ACVR2A, FST or TGFBR3 in granulosa cells and inhibin A or activin A concentrations in follicular fluid. Moreover, the effects of mutations differed between breeds. In cultures of granulosa cells from wild-type ewes, BMP15, acting alone or in synergy with GDF9, stimulated INHA, INHBA and FST expression, but inhibited the expression of TGFBR3 Activin A did not affect INHBA expression, but inhibited the expression of ACVR2A also. The complexity of the inhibin/activin system, including positive and antagonistic elements, and the differential regulation of these elements by BMP15 and activin can explain that the effects of BMP15 mutations differ when present in different genetic backgrounds. In conclusion, the ovarian inhibin/activin system is unlikely to participate in the increase of ovulation rate associated with BMP15 mutations in sheep.

Genome-wide analysis of DNA Methylation profiles on sheep ovaries associated with prolificacy using whole-genome Bisulfite sequencing

“…Moreover, it plays important roles in regulating patterning and morphogenesis that are related to adherent junctions and are required for gonadogenesis [ 42 , 43 ], and similar results were also found in our study, moreover, the DMRs related to CTNNB1 were located in distal intergenic and intron regions (2nd, 4th, 5th of 36). INHBA expression was stimulated by BMP15 in granulosa cells from wild type ewes, and may play roles in the increased ovulation rates [ 44 ], and in our study, INHBA was correlated with FST , LHCGR , FSHR , BMPR1B , TGFB2 and TGFB3 . Up to now, several studies have reported on the function of JUP in ovarian cancers [ 45 – 49 ], but information regarding JUP function in mammal reproduction has been limited, our study supports JUP as being related to oocyte development, as identified GO analysis, and two DMRs (chr11:41,441,802–41,442,083 on the antisense strand, strong hypomethylation in the HP group; chr11:41,458,174–41,458,384 on the antisense strand, strong hypermethylation in the HP group) were related to JUP and located in distal intergenic and intron regions respectively.…”

Whole-Genome Resequencing of Worldwide Wild and Domestic Sheep Elucidates Genetic Diversity, Introgression, and Agronomically Important Loci

“…We found that ROD chr15: 49,000,001–50,000,000 were in concordance with high nonsynonymous to synonymous (N/S) ratio (N/S ratio = 1.49; supplementary table S29, Supplementary Material online). Additionally, 59 SVs under selection during sheep improvement including 1,601 candidate genes ( supplementary table S30, Supplementary Material online), several of which are related to regulation of ovulation rate (e.g., BMP15 and CYP17 ) ( Estienne et al 2017 ).…”

Inhibin as a reproductive biomarker part 2. Clinical significance of inhibins in reproductive medicine

“…В некоторых исследованиях показано, что GDF9 и BMP15 могут влиять на секрецию ингибина и активина [15,21,22]. По некоторым данным, BMP15 может активировать in vitro транскрипцию генов, кодирующих субъединицы ингибина в клетках гранулезы мыши, а взаимодействуя с GDF9, повышает продукцию иммунореактивного ингибина в этих клетках [22].…”

“…По некоторым данным, BMP15 может активировать in vitro транскрипцию генов, кодирующих субъединицы ингибина в клетках гранулезы мыши, а взаимодействуя с GDF9, повышает продукцию иммунореактивного ингибина в этих клетках [22]. Обнаружено, что гетеродимер кумулин, синергически взаимодействуя с ФСГ, стимулирует секрецию ингибинов А, B и активина B [15,21]. При этом по отдельности GDF9 и BMP15 не обладают таким эффектом.…”