A Novel Intergenic ETnII-β Insertion Mutation Causes Multiple Malformations in Mice

English version České info

Mouse early transposon insertions are responsible for ∼10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. In addition, we refined the Ppd genetic interval and discovered a novel ETnII-β early transposon insertion between the genes for Dusp9 and Pnck. The ETn inserted 1.6 kb downstream and antisense to Dusp9 and does not disrupt polyadenylation or splicing of either gene. Knock-in mice engineered to carry the ETn display Ppd characteristic ectopic caudal limb phenotypes, showing that the ETn insertion is the Ppd molecular lesion. Early transposons are actively expressed in the early blastocyst. To explore the consequences of the ETn on the genomic landscape at an early stage of development, we compared interval gene expression between wild-type and mutant ES cells. Mutant ES cell expression analysis revealed marked upregulation of Dusp9 mRNA and protein expression. Evaluation of the 5′ LTR CpG methylation state in adult mice revealed no correlation with the occurrence or severity of Ppd phenotypes at birth. Thus, the broad range of phenotypes observed in this mutant is secondary to a novel intergenic ETn insertion whose effects include dysregulation of nearby interval gene expression at early stages of development.

Vyšlo v časopise: A Novel Intergenic ETnII-β Insertion Mutation Causes Multiple Malformations in Mice. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1003967
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003967

Souhrn

Zdroje

1. WhitelawE, MartinDI (2001) Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet 27: 361–365.

2. PeastonAE, EvsikovAV, GraberJH, de VriesWN, HolbrookAE, et al. (2004) Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Dev Cell 7: 597–606.

3. KleinjanD-J, CoutinhoP (2009) Cis-ruption mechanisms: disruption of cis-regulatory control as a cause of human genetic disease. Briefings in Functional Genomics and Proteomics 8: 317–332.

4. NadeauJH (2009) Transgenerational genetic effects on phenotypic variation and disease risk. Hum Mol Genet 18: R202–10.

5. KunarsoG, ChiaN-Y, JeyakaniJ, HwangC, LuX, et al. (2010) Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 42: 631–634.

6. BernalAJ, JirtleRL (2010) Epigenomic disruption: the effects of early developmental exposures. Birth Def Res (Part A): Clin and Mol Teratol 88: 938–944.

7. NadeauJH, DudleyAM (2011) Systems genetics. Science 331: 1015–16.

8. ChakravartiA, KapoorA (2012) Mendelian puzzles. Science 335: 930–31.

9. MaksakovaIA, RomanishMT, GagnierL, DunnCA, van de LagemaatLN, et al. (2006) Retroviral elements and their hosts: Insertional mutagenesis in the mouse germ line. PLoS Genetics 2: 1–10.

10. BruletP, KaghadM, XuYS, CroissantO, JacobF (1983) Early differential tissue expression of transposon-like repetitive DNA sequences of the mouse. Proc Natl Acad Sci USA 80: 5641–5645.

11. BruletP, CondamineH, JacobF (1985) Spatial distribution of transcripts of the long repeated ETn sequence during early mouse embryogenesis. Proc Natl Acad Sci USA 82: 2054–2058.

12. LoebelDA, TsoiB, WongN, O'RourkeMP, TamPP (2004) Restricted expression of ETn-related sequences during post-implantation mouse development. Gene Expr Patterns 4: 467–471.

13. RakyanVK, BlewittME, DrukerR, PreisJI, WhitelawE (2002) Metastable epialleles in mammals. Trends Genet 18: 348–351.

14. ReissD, ZhangY, RouhiA, ReuterM, MagerDL (2010) Variable DNA methylation of transposable elements: The case study of mouse Early Transposons. Epigenetics 5: 68–79.

15. LehoczkyJ, CaiW-W, DouglasJ, MoranJ, BeierD, et al. (2006) Description and genetic mapping of Polypodia: an X-linked dominant mouse mutant with ectopic caudal limbs and other malformations. Mamm Genome 17: 903–913.

16. KaghadM, MailletL, BruletP (1985) Retroviral characteristics of the long terminal repeat of murine ETn sequences. The EMBO J 4: 2911–2915.

17. SonigoP, Wain-HobsonS, BougueleretL, TiollaisP, JacobF, et al. (1987) Nucleotide sequence and evolution of ETn elements. Proc Natl Acad Sci USA 84: 3768–3771.

18. MagerDL, FreemanJD (2000) Novel mouse type D endogenous proviruses and ETn elements share long terminal repeat and internal sequences. J Virol 74: 7221–7229.

19. BaustC, BaillieGJ, MagerDL (2002) Insertional polymorphisms of ETn retrotransposons include a disruption of the wiz gene in C57BL/6. Mamm Genome 13: 423–428.

20. BaustC, GagnierL, BaillieGJ, HarrisMJ, JuriloffDM, et al. (2003) Structure and expression of mobile ETnII retroelements and their coding-competent MusD relatives in the mouse. J Virol 77: 11448–11458.

21. MaksakovaIA, MagerDL (2005) Transcriptional regulation of early transposon elements, an active family of mouse long terminal repeat retrotransposons. J Virol 79: 13865–13874.

22. KontgenF, SussG, StewartC, SteinmetzM, BluethmannH (1993) Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. Int Immunol 5: 957–964.

23. Van de LagemaatLN, MedstrandP, MagerDL (2006) Multiple effects govern endogenous retrovirus survival patterns in human gene introns. Genome Biol 7: R86.

24. DickinsonRJ, WilliamsDJ, SlackDN, WilliamsonJ, SeternesO-M, et al. (2002) Characterization of a murine gene encoding a developmentally regulated cytoplasmic dual-specificity mitogen-activated protein kinase phosphatase. Biochem J 364: 145–155.

25. DickinsonRJ, KeyseSM (2006) Diverse physiological functions for dual-specificity MAP kinase phosphatases. J Cell Science 119: 4607–4615.

26. ChristieGR, WilliamsDJ, MacIsaacF, DickinsonRJ, RosewellI, et al. (2005) The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development. Mol Cell Biol 25: 8323–8333.

27. LiZ, FeiT, ZhangJ, ZhuG, WangL, et al. (2012) BMP4 signaling acts via dual-specificity phosphatase 9 to control ERK activity in mouse embryonic stem cells. Cell Stem Cell 10: 171–182.

28. GardnerHP, RajanJV, HaSI, CopelandNG, GilbertDJ, et al. (2000) Cloning, characterization, and chromosomal localization of Pnck, a Ca2+/Calmodulin-dependent protein kinase. Genomics 63: 279–288.

29. DebTB, CoticchiaCM, BarndtR, ZuoH, DicksonRB, et al. (2008) Pregnancy-upregulated nonubiquitous calmodulin kinase induces ligand-independent EGFR degradation. 2008. Am J Physiol Cell Physiol 295: C365–C377.

30. ShellBE, CollinsJT, ElenichLA, SzurekPF, DunnickWA (1990) Two subfamilies of murine retrotransposon ETn sequences. Gene 86: 269–274.

31. JohnsonKR, LanePW, Ward-BaileyP, DavissonMT (1995) Mapping the mouse dactylaplasia mutation, Dac, and a gene that controls its expression, mdac. Genomics 29: 457–464.

32. CrackowerMA, MotoyamaJ, TsuiL-C (1998) Defect in the maintenance of the apical ectodermal ridge in the Dactylaplasia mouse. Dev Biol 201: 78–89.

33. SidowA, BulotskyMS, KerrebrockAW, BirrenBW, AltshulerD, et al. (1999) A novel member of the F-box/WD40 gene family encoding dactylin, is disrupted in the mouse dactylaplasia mutant. Nat Genet 23: 104–107.

34. KanoH, KurahashiH, TodaT (2007) Genetically regulated epigenetic transcriptional activation of retrotransposon insertion confers mouse dactylaplasia phenotype. Proc Natl Acad Sci USA 104: 19034–19039.

35. SembaK, ArakiK, MatsumotoK-I, SudaH, AndoT, et al. (2013) Ectopic expression of Ptf1a induces spinal defects, urogenital defects, and anorectal malformations in Danforth's Short Tail mice. PLoS Genetics 9 (2) e1003204.

36. VlangosCN, SiuniakAN, RobinsonD, ChinnaiyanAM, LyonsRH, et al. (2013) Next generation sequencing identifies the Danforth's short tail mutation as a retrotransposon insertion affecting Ptf1a expression. PLoS Genetics 9 (2) e1003205.

37. LuganiF, AroraR, PapetaN, PatelA, ZhengZ, et al. (2013) A retrotransposon insertion in the 5′ regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's Short Tail mouse. PLoS Genetics 9 (2) e1003206.

38. HummelKP (1958) The inheritance and expression of Disorganization, an unusual mutation in the mouse. J Exp Zool 137: 389–423.

39. HummelKP (1959) Developmental anomalies in mice resulting from the action of the gene, Disorganization, a semi-dominant lethal. Pediatrics 23: 212–221.

40. CrosbyJL, VarnumDS, WashburnLL, NadeauJH (1992) Disorganization is a completely dominant gain of function mouse mutation causing sporadic developmental defects. Mech Dev 37: 121–126.

41. RobinNH, AbbadiN, McCandlessSE, NadeauJH (1997) Disorganization in mice and humans and it relation to sporadic birth defects. Amer J Med Gen 73: 425–436.

42. DanforthCH (1925) Hereditary doubling suggesting anomalous chromatin distribution in the mouse. Proc Soc Exp Biol & Med 23: 145–147.

43. DanforthCH (1930) Developmental anomalies in a special strain of mice. Am J Anat 45: 275–287.

44. Center EM (1969) Morphology and embryology of Duplicitas posterior mice. Teratology 2: 377–388.

45. RutledgeJC, ShourbajiAG, HughesLA, PolifkaJE, CruzYP, et al. (1994) Limb and lower-body duplications induced by retinoic acid in mice. Proc Natl Acad Sci USA 91: 5436–5440.

46. RutledgeJC (1997) Developmental toxicity induced during early stages of mammalian embryogenesis. Mut Res 396: 113–127.

47. NiederreitherK, WardSJ, DolleP, ChambonP (1996) Morphological and molecular characterization of retinoic acid-induced limb duplications in mice. Dev Biol 176: 185–198.

48. LiaoX, CollinsMD (2008) All-trans retinoic acid-induced ectopic limb and caudal structures: murine strain sensitivities and pathogenesis. Dev Dyn 237: 1553–1564.

49. Vogt H. Das Bild des Kranken. Die Darstellung Ausserer Veranderungen Durch Innere Leiden Und Ihrer Heilmassnahmen Von Der Renaissance Bis In Unsere Zeit. J.F. Lehmanns, Verlag, Munchen. page 155.

50. WeisselbergB, Ben-AmiT, GoodmanRM (1988) Partial duplication of the lower limb with agenesis of ipsilateral kidney - a new syndrome: report of a case and review of the literature. Clin Gen 33: 234–239.

51. Stevenson RE, Hall JG, Goodman RM, eds. (1993) Human Malformations and Related Anomalies. Volumes I and II. Oxford Monographs on Medical Genetics No. 27.

52. BillettDM, BearJN (1978) Partial duplication of the lower limb. The J Bone Joint Surg 60A: 1143–1145.

53. TaniguchiK, AokiY, KurimotoH, OkamuraT (1975) Baby with a third leg. J Ped Surg 10: 143–144.

54. PetzelMA, EricksonRP (1991) Disorganisation: a possible cause of apparent conjoint twinning. J Med Genetics 28: 712–714.

55. La TorreR, FusaroP, AnceschiMM, Montanino-OlivaM, ModestoS, et al. (1998) Unusual case of caudal duplication (Dipygus). J Clin Ultrasound 26: 163–165.

56. Delgado-LuengoWN, RodriquezMLH, PirelaIV, FerrerSG, CoronaPE, et al. (2004) Human Disorganization complex, as a polytopic blastogenesis defect: A new case. Am J Med Gen 125A: 181–185.

57. WangC, CampbellS, FurnerR, HillD (1980) Disposition of all-trans and 13-cis-retinoic acids and N-hydroxy-ethylretinamide in mice after intravenous administration. Drug Metab Dispos 8: 8–11.

58. WardSJ, Morriss-KayGM (1995) Distribution of all-trans-, 13-cis- and 9-cis-retinoic acid to whole rat embryos and maternal serum following oral administration of a teratogenic dose of all-trans-retinoic acid. Pharm Toxicol 76: 196–201.

59. FinkL, SeegerW, ErmertL, HanzeJ, StahlU, et al. (1998) Real-time quantitative RT-PCR after laser-assisted cell picking. Nat Med 4: 1329–1333.

60. Hughes ED, Saunders TL (2011) Gene Targeting in Embryonic Stem Cells in “Advanced Protocols for Animal Transgenesis: An ISTT Manual”, Pease SS and Saunders TL (eds), Springer, Berlin.

61. IrizarryRA, HobbsB, CollinF, et al. (2003) Exploration, normalization and summaries of high density oligonucleotide array probe level data. Biostatistics 4: 249–264.

62. SmythGK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl In Genet Mol Biology 3: Article 3.

63. RitchieME, DiyagamaD, NielsonJ, et al. (2006) Empirical array quality weights in the analysis of microarray data. BMC Bioinf 7: 261–277.

64. BenjaminiY, HochbergY (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc, Series B 57: 289–300.