绵羊骨形态发生蛋白受体-1B基因研究进展

doi:10.16431/j.cnki.1671-7236.2024.02.021

摘要/Abstract

摘要： 绵羊繁殖性能在绵羊产业中有着重要意义,除通过一些技术手段(如同期发情、人工授精、超数排卵等)之外,在目前已知的关于能够提高绵羊繁殖力的16个基因共20个突变体当中,以骨形态发生蛋白受体-1B(bone morphogenetic protein receptor type-1B,BMPR-1B)基因对绵羊繁殖力的影响最大。BMPR-1B基因是世界上第一个被发现的多羔主效基因,其编码区的A746G突变导致蛋白质序列中第249位的谷氨酰胺被置换为精氨酸(Q249R),最终能够引起绵羊排卵数和产羔数增加。作者介绍了绵羊多羔主效基因BMPR-1B及其突变体FecB(A746G)的发现与结构,简述了该基因分子方面的作用机理,对BMP/Smad信号通路的调控以及与绵羊繁殖之间的联系,并简单分析了FecB突变后对绵羊卵巢、卵泡等组织细胞功能,激素调节和相关基因表达的影响。进一步加深对BMPR-1B基因的了解,为研究人员探明该基因诱使绵羊等动物提高产羔数的调控机制,相关配体、调控因子和上下游信号蛋白的影响以及加快哺乳动物高效育种繁殖、扩大种群规模和多胎品系的建立,增加养殖人员的经济收入等提供一些参考和帮助。

关键词: 骨形态发生蛋白受体-1B(BMPR-1B); FecB; 绵羊

Abstract: Sheep reproductive performance holds significant importance in the sheep industry.In addition to various technical methods such as periodic estrus, artificial insemination, and superovulation, among the 20 mutations of 16 genes known to enhance sheep reproductive performance, the bone morphogenetic protein receptor type-1B (BMPR-1B) gene exhibits the most profound impact.BMPR-1B gene stands as the pioneering major lambing gene discovered worldwide.The A746G mutation within the coding region of BMPR-1B gene leads to arginine substitution for glutamine at position 249 in the protein sequence (Q249R), ultimately resulting in increased ovulations and lambs.This paper presents an introduction to the discovery and structure of BMPR-1B gene along with its mutant FecB (A746G).It briefly elucidates on the molecular mechanism of this gene, regulation of BMP/Smad signaling pathway, relationship between sheep reproduction, and provides a concise analysis on how FecB mutation affects ovarian function, follicles, other tissues, hormone regulation and related gene expression in sheep.Further comprehension of BMPR-1B gene will offer valuable insights for researchers exploring regulatory mechanisms inducing increased lambing numbers in sheep and other animals through manipulation of related ligands, regulatory factors as well as upstream and downstream signal proteins.Additionally it can accelerate efficient breeding and reproduction processes among mammals by expanding population size through establishment of multiple litter strains thereby increasing farmers’ economic income.

Key words: bone morphogenetic protein receptor type-1B (BMPR-1B); FecB; sheep

中图分类号:

S813

杨初蕾, 李星瑶, 张译元, 唐红, 郭延华, 王立民, 周平. 绵羊骨形态发生蛋白受体-1B基因研究进展[J]. 中国畜牧兽医, 2024, 51(2): 649-658.

YANG Chulei, LI Xingyao, ZHANG Yiyuan, TANG Hong, GUO Yanhua, WANG Limin, ZHOU Ping. Research Progress on Bone Morphogenetic Protein Receptor Type-1B Gene in Sheep[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(2): 649-658.

参考文献

[1] 南景东,陈国旺,张建胜,等.绵羊多胎基因研究现状[J].现代畜牧兽医,2022,11:75-78. NAN J D,CHEN G W,ZHANG J S,et al.Research status of prolificacy gene in sheep[J].Modern Journal of Animal Husbandry and Veterinary Medicine,2022,11:75-78.(in Chinese)
[2] CHU M X,JIA L H,ZHANG Y J,et al.Polymorphisms of coding region of BMPR-1B gene and their relationship with litter size in sheep[J].Molecular Biology Reports,2011,38:4071-4076.
[3] JIA J L,CHEN Q,GUI L S,et al.Association of polymorphisms in bone morphogenetic protein receptor-1B gene exon-9 with litter size in Dorset,Mongolian,and Small Tail Han ewes[J].Asian-Australasian Journal of Animal Sciences,2019,32:949-955.
[4] 吴翠玲,赵卓,赵云辉,等.母羊多胎基因研究进展[J].黑龙江畜牧兽医,2018,11:68-71. WU C L,ZHAO Z,ZHAO Y H,et al.Research progress of fecundity genes in ewe[J].Heilongjiang Animal Science and Veterinary Medicine,2018,11:68-71.(in Chinese)
[5] 李闯,柳海星,高见红,等.羊主效多胎基因的研究现状[J].延边大学农学学报,2018,40(1):87-93. LI C,LIU H X,GAO J H,et al.A research progress onmajor prolificacy genes in sheep[J].Agricultural Science Journal of Yanbian University,2018,40(1):87-93.(in Chinese)
[6] 王万兴,蔡树东,潘伊微,等.影响肉羊繁殖力的主要候选基因研究进展[J].黑龙江动物繁殖,2021,29(6):20-25. WANG W X,CAI S D,PAN Y W,et al.Research progress on the key genes related to the reproductivity of mutton sheep[J].Heilongjiang Journal of Animal Reproduction,2021,29(6):20-25.(in Chinese)
[7] MONTGOMERY G W,LORD E A,PENTY J M,et al.The Booroola fecundity (FecB) gene maps to sheep chromosome 6[J].Genomics,1994,22(1):148.
[8] MONTGOMERY G W,PENTY J M,LORD E A,et al.The search for the Booroola (FecB) mutation[J]. Journal of Reproduction and Fertility,1995,49:113-121.
[9] MISHRA A K,ARORA A L,KUMAR S,et al.Studies on effect of Booroola (FecB) genotype on lifetime ewes'productivity efficiency,litter size and number of weaned lambs in Garole×Malpura sheep[J].Animal Reproduction Science,2009,113:293-298.
[10] ABDOLI R,ZAMANI P,DELJOU A,et al.Association of BMPR-1B and GDF9 genes polymorphisms and secondary protein structure changes with reproduction traits in Mehraban ewes[J].Gene,2013,524:296-303.
[11] SOUZA C J.The Booroola (FecB) phenotype is associated with a mutation in the bone morphogenetic receptor type 1B (BMPR1B) gene[J].Journal of Endocrinology,2001,169:R1-R6.
[12] 潘章源,狄冉,刘秋月,等.绵羊BMPR1B基因生物信息学分析[J].中国草食动物科学,2015,35(6):1-5. PAN Z Y,DI R,LIU Q Y,et al.Bioinformatics analysis on BMPR1B gene of sheep[J].China Herbivore Science,2015,35(6):1-5.(in Chinese)
[13] MULSANT P,LECERF F,FABRE S,et al.Mutation in bone morphogenetic protein receptor-1B is associated with increased ovulation rate in Booroola Mérino ewes[J].Proceedings of the National Academy of Sciences of the United States of America,2001,98:5104-5109.
[14] ORAON T,SINGH D K,GHOSH M,et al.Allelic and genotypic frequencies in polymorphic booroola fecundity gene and their association with multiple birth and postnatal growth in Chhotanagpuri sheep[J].Veterinary World,2016,9:1294-1299.
[15] KUMAR S,MISHRA A K,KOLTE A P,et al.Screening for booroola (FecB) and galway (FecXG) mutations in Indian sheep[J].Small Ruminant Research,2008,80(1-3):57-61.
[16] MAHDAVI M,NANEKARANI S,HOSSEINI S D.Mutation in BMPR-1B gene is associated with litter size in Iranian Kalehkoohi sheep[J].Animal Reproduction Science,2014,147(3-4):93-98.
[17] WANG X Y,GUO X F,HE X Y,et al.Effects of FecB mutation on estrus,ovulation,and endocrine characteristics in Small Tail Han sheep[J].Frontiers in Veterinary Science,2021,8:709737.
[18] 喇永富,李发弟,杨勤,等.FecB基因在5个中国地方绵羊品种中的多态性及其与产羔数的关联分析[J].中国草食动物科学,2020,40(2):12-17. LA Y F,LI F D,YANG Q,et al.Genetic polymorphism of FecB gene and effect in five Chinese local sheep breeds[J].China Herbivore Science,2020,40(2):12-17.(in Chinese)
[19] CHONG Y Q,JIANG X P,LIU G Q.An ancient positively selected BMPR1B missense variant increases litter size of Mongolian sheep populations following latitudinal gradient[J].Molecular Genetics and Genomics,2022,297:155-167.
[20] 柏雪梅,薛亚欣,邢凤,等.策勒黑羊和多浪羊FecB基因多态性及其与产羔数的相关性研究[J].黑龙江畜牧兽医,2020,1:7-10. BAI X M,XUE Y X,XING F,et al.Association of FecB gene polymorphism with litter size in Cele Black sheep and Duolang sheep[J].Heilongjiang Animal Science and Veterinary Medicine,2020,1:7-10.(in Chinese)
[21] 王琼,马海玉,刘玲玲,等.GDF9、BMPR1B与BMP15基因在和田羊群体的遗传特征分析[J].草食家畜,2020,4:1-8. WANG Q,MA H Y,LIU L L,et al.Analysis on the genetic characteristics of GDF9,BMPR1B and BMP15 gene in Hotan sheep population[J].Grass-Feeding Livestock,2020,4:1-8.(in Chinese)
[22] WILSON T,WU X Y,JUENGEL J L,et al.Highly prolific booroola sheep have a mutation in the intracellular kinase domain of bone morphogenetic protein 1B receptor (ALK-6) that is expressed in both oocytes and granulosa cells[J].Biology of Reproduction,2001,64(4):1225-1235.
[23] 李国忠.绵羊低丰度FecB基因检测方法的建立和BMPR-1B基因打靶的研究[D].石河子:石河子大学,2017. LI G Z.Establishment of a detection method for low abundance FecB gene in sheep and study on BMPR-1B gene targeting in sheep[D].Shihezi:Shihezi University,2017.(in Chinese)
[24] HUSE M,CHEN Y G,MASSAGUÉ J,et al.Crystal structure of the cytoplasmic domain of the type 1 TGF beta receptor in complex with FKBP12[J].Cell,1999,96:425-436.
[25] 龚一鸣,王翔宇,贺小云,等.绵羊FecB突变对BMPR1B活性及BMP/Smad通路的影响研究进展[J].遗传,2023,45(4):295-305. GONG Y M,WANG X Y,HE X Y,et al.Progress on the effect of FecB mutation on BMPR1B activity and BMP/Smad pathway in sheep[J].Hereditas,2023,45(4):295-305.(in Chinese)
[26] JIA J L,JIN J P,CHEN Q,et al.Eukaryotic expression,Co-IP and MS identify BMPR-1B protein-protein interaction network[J].Biological Research,2020,53:24.
[27] 贾建磊,陈倩,靳继鹏,等.绵羊BMPR1B基因真核表达及产物互作蛋白的鉴定[J].生物技术通报,2019,35(12):94-104. JIA J L,CHEN Q,JIN J P,et al.Eukaryotic expression of BMPR1B in sheep and identification of its interaction proteins[J].Biotechnology Bulletin,2019,35(12):94-104.(in Chinese)
[28] 李芝丰.FecB^BB型和FecB⁺⁺型小尾寒羊卵泡期和黄体期输卵管转录组表达分析[D].扬州:扬州大学,2021. LI Z F.Transcriptome analysis of follicular and luteal oviducts of Small Tail Han sheep witth FecB^BB and FecB⁺⁺ genotypes[D].Yangzhou:Yangzhou University,2021.(in Chinese)
[29] YAO Y L,REHEMAN A W E,XU Y F,et al.miR-125b contributes to ovarian granulosa cell apoptosis through targeting BMPR1B,a major gene for sheep prolificacy[J].Reproductive Sciences,2019,26:295-305.
[30] YAO Y L,NIU J Q,SIZHU S L,et al.microRNA-125b regulates apoptosis by targeting bone morphogenetic protein receptor 1B in yak granulosa cells[J].DNA and Cell Biology,2018,37:878-887.
[31] ABDURAHMAN A,AIERKEN W,ZHANG F,et al.miR-1306 induces cell apoptosis by targeting BMPR1B gene in the ovine granulosa cells[J].Frontiers in Genetics,2022,13:989912.
[32] KUMAR S,PUNETHA M,JOSE B,et al.Modulation of granulosa cell function via CRISPR-Cas fuelled editing of BMPR-1B gene in goats (Capra hircus)[J].Scientific Reports,2020,10:20446.
[33] 王雪,张景萍,郭丽丽,等.TGF-β/Smad信号通路在哺乳动物卵巢发育调控中的作用研究进展[J].中国畜牧杂志,2023,59(3):61-69. WANG X,ZHANG J P,GUO L L,et al.Research progress on the regulation of TGF-β/Smad signaling pathway in mammalian ovarian development[J].Chinese Journal of Animal Science,2023,59(3):61-69.(in Chinese)
[34] QI M Y,XU L Q,ZHANG J N,et al.Effect of the Booroola fecundity (FecB) gene on the reproductive performance of ewes under assisted reproduction[J].Theriogenology,2020,142:246-250.
[35] 张筱艳.绵羊BMPR1B基因SNP和血液BMPR1B蛋白与繁殖性能的相关性研究[D].兰州:甘肃农业大学,2020. ZHANG X Y.Study of the effects of BMPR1B gene SNP and the quantity of BMPR1B protein in blood on reproductive performance of sheep[D].Lanzhou:Gansu Agricultural University, 2020.(in Chinese)
[36] 于洋,梁小军,马吉锋,等.滩湖F2代FecB基因的多态性检测[J].上海畜牧兽医通讯,2018,4:44-45. YU Y,LIANG X J,MA J F,et al.Polymorphism detection of FecB gene in the F2 generation of hybrid Tan sheep and Hu sheep[J].Shanghai Journal of Animal Husbandry and Veterinary Medicine,2018,4:44-45.(in Chinese)
[37] WU J,CHEN X,SEHGAL P,et al.Arginine methylation of R81 in Smad6 confines BMP-induced Smad1 signaling[J].Journal of Biological Chemistry,2021,296:100496.
[38] LI M N,LIANG W W,ZHU C Y,et al.Smad4 mediates BMF involvement in sheep granulosa cell apoptosis[J].Gene,2022,817:146231.
[39] XIE L L,MIAO X Y,LUO Q M,et al.Impact of FecB mutation on ovarian DNA methylome in Small-Tail Han sheep[J].Genes (Basel),2023,14:203.
[40] ESTIENNE A,PIERRE A,DI CLEMENTE N,et al.Anti-müllerian hormone regulation by the bone morphogenetic proteins in the sheep ovary:Deciphering a direct regulatory pathway[J].Endocrinology,2015,156:301-313.
[41] JIANG Y,XIE M,CHEN W B,et al.The sheep genome illuminates biology of the rumen and lipid metabolism[J].Science,2014,344:1168-1173.
[42] GLISTER C,KEMP C F,KNIGHT P G.Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells:Actions of BMP-4,-6 and-7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin[J].Reproduction,2004,127:239-254.
[43] XU Y F,LI E L,HAN Y D,et al.Differential expression of mRNAs encoding BMP/Smad pathway molecules in antral follicles of high-and low-fecundity Hu sheep[J].Animal Reproduction Science,2010,120:47-55.
[44] BAHIRE S V,RAJPUT P K,KUMAR V,et al.Quantitative expression of mRNA encoding BMP/Smad signalling genes in the ovaries of Booroola carrier and non-carrier GMM sheep[J].Reproduction in Domestic Animals,2019,54:1375-1383.
[45] 汤继顺,胡文萍,狄冉,等.多羔候选基因BMPR1B、BMP15和GDF9在绵羊黄体期组织中的表达分析[A].2018年全国养羊生产与学术研讨会[C].2018. TANG J S,HU W P,DI R,et al.Expression analysis of multi-lamb candidate genes BMPR1B,BMP15 and GDF9 in luteal stage tissues of sheep[A].2018 National Sheep Production and Academic Seminar[C].2018.(in Chinese)
[46] 刘霜,郑杰,卢建远,等.山羊卵巢中BMP15、GDF9和BMPR1B基因的表达量研究[J].畜牧与兽医,2016,5:5. LIU S,ZHENG J,LU J Y,et al.The mRNA expression levels of BMP15,GDF9 and BMPR1B in goat ovaries[J].Animal Husbandry&Veterinary Medicine,2016,5:5.(in Chinese)
[47] MIAO X Y,LUO Q M,ZHAO H J,et al.Ovarian proteomic study reveals the possible molecular mechanism for hyperprolificacy of Small Tail Han sheep[J].Scientific Reports,2016,6:27606.
[48] 杨华,陈新华,李爱芳,等.多胎主效基因在绵羊育种和生产实践中的应用[J].新疆农垦科技,2010,33(3):42-43. YANG H,CHEN X H,LI A F,et al.Application of multiple major genes in sheep breeding and production practice[J].Xinjiang Farm Research of Science and Technology,2010,33(3):42-43.(in Chinese)
[49] BAIRD D T,CAMPBELL B K.Follicle selection in sheep with breed differences in ovulation rate[J].Molecular and Cellular Endocrinology,1998,145:89-95.
[50] CAMPBELL B K,BAIRD D T,SOUZA C J,et al.The FecB(Booroola) gene acts at the ovary:In vivo evidence[J].Reproduction,2003,126:101-111.
[51] READER K L,HAYDON L J,LITTLEJOHN R P,et al.Booroola BMPR1B mutation alters early follicular development and oocyte ultrastructure in sheep[J].Reproduction Fertility and Development,2012,24:353-361.
[52] HEATH D A,CALDANI M,MCNATTY K P.Relationship between the number of immunostaining gonadotropes and the plasma concentrations of gonadotrophins in ewes with and without the FecB gene[J]. Journal of Reproduction and Fertility,1996,106:73-78.
[53] SHIMASAKI S,MOORE R K,OTSUKA F,et al.The bone morphogenetic protein system in mammalian reproduction[J].Endocrine Reviews,2004,25:72-101.
[54] XIA Y,O'SHEA T,MURISON R,et al.Concentrations of progesterone,follistatin,and follicle-stimulating hormone in peripheral plasma across the estrous cycle and pregnancy in merino ewes that are homozygous or noncarriers of the Booroola gene[J].Biology of Reproduction,2003,69:1079-1084.
[55] JUENGEL J L,DAVIS G H,MCNATTY K P.Using sheep lines with mutations in single genes to better understand ovarian function[J].Reproduction,2013,146:R111-R123.
[56] MCNATTY K P,HEATH D A,HUDSON N L,et al.Gonadotrophin-responsiveness of granulosa cells from bone morphogenetic protein 15 heterozygous mutant sheep[J].Reproduction,2009,138:545-551.
[57] KUMAR S,RAJPUT P K,BAHIRE S V,et al.Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep[J].Systems Biology in Reproductive Medicine,2020,66:185-201.
[58] MIAO X Y,QIN Q M,LUO X Y.Genome-wide transcriptome analysis of mRNAs and microRNAs in Dorset and Small Tail Han sheep to explore the regulation of fecundity[J].Molecular and Cellular Endocrinology,2015,402:32-42.
[59] SEJIAN V,MAURYA V P,PRINCE L L L,et al.Effect of FecB status on the allometric measurements and reproductive performance of Garole×Malpura ewes under hot semi-arid environment[J].Tropical Animal Health and Production,2015,47:1089-1093.
[60] 张也,艾日夏提·地里夏提,刘志强,等.FecB基因对杜泊羊和湖羊杂交后代产羔率与生长性能的影响[J].中国草食动物科学,2021,41(2):69-72. ZHANG Y,AIRIXIATI·DILIXIATI,LIU Z Q,et al.Effect of FecB gene on lambing percentage and growth performance of cross offspring of Doper and Hu sheep[J].China Herbivore Science,2021,41(2):69-72.(in Chinese)
[61] 陈洋,孙丽敏,陈辉,等.南非肉用美利奴羊与东北细毛羊杂交一代6号染色体微卫星DNA多态性研究[J].中国畜牧杂志,2015,51(17):10-16. CHEN Y,SUN L M,CHEN H,et al.Studies on microsatemte DNA polymorphisms of chromosome 6 in hybrid sheep[J].Chinese Journal of Animal Science,2015,51(17):10-16.(in Chinese)
[62] 马丽娜,于洋.滩羊多胎基因(FecB)TaqMan探针SNP分型与产羔数的关联研究[J].畜牧与饲料科学,2017,38(3):20-22. MA L N,YU Y.Correlation analysis between fecundity gene (FecB) SNP genotyping by TaqMan probe and litter size in Tan sheep[J].Animal Husbandry and Feed Science,2017,38(3):20-22.(in Chinese)
[63] FABRE S,PIERRE A,MULSANT P,et al.Regulation of ovulation rate in mammals:Contribution of sheep genetic models[J].Reproductive Biology and Endocrinology,2006,4:20.
[64] SHIMIZU K,NAKAMURA T,BAYASULA,et al.Molecular mechanism of FSHR expression induced by BMP15 in human granulosa cells[J].Journal of Assisted Reproduction and Genetics,2019,36:1185-1194.
[65] MCNATTY K P,HEATH D A,CLARK Z,et al.Ovarian characteristics in sheep with multiple fecundity genes[J].Reproduction,2017,153:233-240.