Mammalian Genome

, Volume 30, Issue 1–2, pp 34–41 | Cite as

A miR-18a binding-site polymorphism in CDC42 3′UTR affects CDC42 mRNA expression in placentas and is associated with litter size in pigs

  • Ruize Liu
  • Dadong Deng
  • Xiangdong Liu
  • Yujing Xiao
  • Ji Huang
  • Feiyu Wang
  • Xinyun Li
  • Mei YuEmail author


Increasing evidence suggests that miRNA binding-site polymorphism in the 3′-untranslated region (3′UTR) of a target gene could affect that gene’s expression, and can be associated with a variety of complex traits. In this study, we find that miR-18a and cell division cycle 42 (CDC42) mRNA, whose expression was inversely correlated, are differentially expressed in porcine placentas during critical stages of placental development. rs55618224 (T>C), a SNP in the 3′UTR region of CDC42 that is perfectly complementary to the miR-18a seed could influence miR-18a-related regulation of CDC42 gene by altering their binding affinity. In addition, CDC42 mRNA was found to have higher expression level in the homozygous TT placentas as compared to those homozygous CC placentas in pigs. Furthermore, we identified a significant association between rs55618224 and total number born per litter. These results suggest the miR-18a binding-site polymorphism in CDC42 3′UTR may impact litter size by regulation of CDC42 gene in porcine placentas.



This work was funded by the Natural Science Foundation of China (31572370), Natural Science Foundation of Hubei Province (Grant# 2018CFA015), Fundamental Research Funds for the Central Universities (Program No. 2662018PY037), and HZAU pre-research project of China. The authors thank Dr. Sean Simmons from Broad institute of MIT and Harvard for helpful language modification.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

335_2018_9788_MOESM1_ESM.docx (89 kb)
Supplementary material 1 (DOCX 90 KB)


  1. Agarwal V, Bell GW, Nam J-W, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. elife 4:e05005CrossRefGoogle Scholar
  2. Ambros V (2004) The functions of animal microRNAs. Nature 431:350CrossRefGoogle Scholar
  3. An X et al (2015) Single-nucleotide polymorphisms g. 151435C> T and g. 173057T> C in PRLR gene regulated by bta-miR-302a are associated with litter size in goats. Theriogenology 83:1477–1483.e1471CrossRefGoogle Scholar
  4. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism and function. Cell 116:281–297CrossRefGoogle Scholar
  5. Bidarimath M, Tayade C (2017) Pregnancy and spontaneous fetal loss: a pig perspective. Mol Reprod Dev 84(9):856–869CrossRefGoogle Scholar
  6. Brest P et al (2011) A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet 43:242CrossRefGoogle Scholar
  7. Chang WL et al (2018) PLAC8, a new marker for human interstitial extravillous trophoblast cells, promotes their invasion migration. Development. Google Scholar
  8. Clop A et al (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38:813CrossRefGoogle Scholar
  9. Colombié N, Choesmel-Cadamuro V, Series J, Emery G, Wang X, Ramel D (2017) Non-autonomous role of Cdc42 in cell-cell communication during collective migration. Dev Biol 423:12–18CrossRefGoogle Scholar
  10. Covarrubias-Pazaran G (2016) Genome-assisted prediction of quantitative traits using the R package sommer. PLoS ONE 11:e0156744CrossRefGoogle Scholar
  11. Dantzer V (1985) Electron microscopy of the initial stages of placentation in the pig. Anat Embryol (Berl) 172:281–293CrossRefGoogle Scholar
  12. Dehapiot B, Carrière V, Carroll J, Halet G (2013) Polarized Cdc42 activation promotes polar body protrusion and asymmetric division in mouse oocytes. Dev Biol 377:202–212CrossRefGoogle Scholar
  13. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629CrossRefGoogle Scholar
  14. Grimson A, Farh KK-H, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105CrossRefGoogle Scholar
  15. Hernandez SC, Finlayson HA, Ashworth CJ, Haley CS, Archibald AL (2014) A genome-wide linkage analysis for reproductive traits in F2 Large White x Meishan cross gilts. Anim Genet 45:191–197. CrossRefGoogle Scholar
  16. Hong L, Hou C, Li X, Li C, Zhao S, Yu M (2014) Expression of heparanase is associated with breed-specific morphological characters of placental folded bilayer between Yorkshire and Meishan pigs. Biol Reprod 90:56. CrossRefGoogle Scholar
  17. Hong L et al (2017) E-cadherin and ZEB2 modulate trophoblast cell differentiation during placental development in pigs. Reproduction 154:765–775. CrossRefGoogle Scholar
  18. Humphreys KJ, McKinnon RA, Michael MZ (2014) miR-18a inhibits CDC42 and plays a tumour suppressor role in colorectal cancer cells. PLoS ONE 9:e112288CrossRefGoogle Scholar
  19. Krawczynski K, Najmula J, Bauersachs S, Kaczmarek MM (2015) MicroRNAome of porcine conceptuses and trophoblasts: expression profile of micrornas and their potential to regulate genes crucial for establishment of pregnancy. Biol Reprod 92:21. CrossRefGoogle Scholar
  20. Lee D-G, Nam J, Kim SW, Kang Y-M, An HJ, Kim CW, Choi J-S (2015) Proteomic analysis of reproduction proteins involved in litter size from porcine placenta. Biosci Biotechnol Biochem 79:1414–1421CrossRefGoogle Scholar
  21. Li H et al (2015) Integrated analysis of miRNA/mRNA network in placenta identifies key factors associated with labor onset of Large White and Qingping sows. Sci Rep 5:13074. CrossRefGoogle Scholar
  22. Li J et al (2017) Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development. Dev Biol 421:271–283CrossRefGoogle Scholar
  23. Liu S, Li Q, Na Q, Liu C (2012) Endothelin-1 stimulates human trophoblast cell migration through Cdc 42 activation. Placenta 33:712–716CrossRefGoogle Scholar
  24. Liu R, Wang M, Su L, Li X, Zhao S, Yu M (2015) The expression pattern of MicroRNAs and the associated pathways involved in the development of porcine placental folds that contribute to the expansion of the exchange surface. Area Biol Reprod 93:62. Google Scholar
  25. Ma C et al (2016) miR-762 promotes porcine immature Sertoli cell growth via the ring finger protein 4 (RNF4 gene). Sci Rep 6:32783CrossRefGoogle Scholar
  26. Maier R et al (2015) Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. Am J Hum Genet 96:283–294CrossRefGoogle Scholar
  27. Mendell JT (2008) miRiad roles for the miR-17-92 cluster in development and disease. Cell 133:217–222CrossRefGoogle Scholar
  28. Moszyńska A, Gebert M, Collawn JF, Bartoszewski R (2017) SNPs in microRNA target sites and their potential role in human disease. Open Biol 7:170019CrossRefGoogle Scholar
  29. Nicola C, Lala PK, Chakraborty C (2008) Prostaglandin E2-mediated migration of human trophoblast requires RAC1 and CDC42. Biol Reprod 78:976–982. CrossRefGoogle Scholar
  30. Pirooz HJ et al (2017) Functional SNP in microRNA-491-5p binding site of MMP9 3′-UTR affects cancer susceptibility. J Cell Biochem 119(7):5126–5134Google Scholar
  31. Rempel LA, Freking BA, Miles JR, Nonneman DJ, Rohrer GA, Vallet JL, Schneider JF (2011) Association of porcine heparanase and hyaluronidase 1 and 2 with reproductive and production traits in a Landrace–Duroc–Yorkshire population. Front Genet 2:20CrossRefGoogle Scholar
  32. Roy J, Mallick B (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3′ UTR microRNA response elements. Genomics 109:177–185CrossRefGoogle Scholar
  33. Shao G, Luo L, Jiang S, Deng C, Xiong Y, Li F (2011) AC/T mutation in microRNA target sites in BMP5 gene is potentially associated with fatness in pigs. Meat Sci 87:299–303CrossRefGoogle Scholar
  34. Su L, Zhao S, Zhu M, Yu M (2010) Differential expression of microRNAs in porcine placentas on days 30 and 90 of gestation. Reprod Fertil Dev 22:1175–1182. CrossRefGoogle Scholar
  35. Tak YG, Farnham PJ (2015) Making sense of GWAS: using epigenomics and genome engineering to understand the functional relevance of SNPs in non-coding regions of the human genome. Epigenet Chromatin 8:57CrossRefGoogle Scholar
  36. Vallet JL, Freking BA (2007) Differences in placental structure during gestation associated with large and small pig fetuses. J Anim Sci 85:3267–3275. CrossRefGoogle Scholar
  37. Vallet JL, Miles JR, Freking BA (2009) Development of the pig placenta Soc. Reprod Fertil Suppl 66:265–279Google Scholar
  38. Vallet JL, Miles JR, Freking BA (2010) Effect of fetal size on fetal placental hyaluronan and hyaluronoglucosaminidases throughout gestation in the pig. Anim Reprod Sci 118:297–309CrossRefGoogle Scholar
  39. Vallet J, McNeel A, Johnson G, Bazer F (2013) Triennial reproduction symposium: limitations in uterine and conceptus physiology that lead to fetal losses. J Anim Sci 91:3030–3040CrossRefGoogle Scholar
  40. Wang S-m, Zeng W-x, Wu W-s, Sun L-l, Yan D (2018) Association between a microRNA binding site polymorphism in SLCO1A2 and the risk of delayed methotrexate elimination in Chinese children with acute lymphoblastic leukemia. Leuk Res 65:61–66CrossRefGoogle Scholar
  41. Zhang Y, Wang Q-C, Liu J, Xiong B, Cui X-S, Kim N-H, Sun S-C (2017) The small GTPase CDC42 regulates actin dynamics during porcine oocyte maturation. J Reprod Dev 63:505–510CrossRefGoogle Scholar
  42. Zhu X-m, Han T, Sargent IL, Yin G-w, Yao Y-q (2009) Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies. Am J Obstet Gynecol 200:661.e661–661.e667CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ruize Liu
    • 1
  • Dadong Deng
    • 1
  • Xiangdong Liu
    • 1
  • Yujing Xiao
    • 1
  • Ji Huang
    • 1
  • Feiyu Wang
    • 1
  • Xinyun Li
    • 1
  • Mei Yu
    • 1
    Email author
  1. 1.Key Lab of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of EducationHuazhong Agricultural UniversityWuhanChina

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