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Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway


Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XYB6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a YAKR chromosome replaced the YB6 chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/− B6 XYAKR, Wt1+/− B6 XYAKR, B6 XYPOS, and B6 XYAKR fetuses. We propose that Wt1B6 and Sf1B6 are hypomorphic alleles of testis-determining pathway genes and that Wnt4B6 is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1B6 and/or Sf1B6 alleles that compromise testis differentiation and a Wnt4B6 allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a “weak” Sry allele, such as the one on the YPOS chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal.


Vyšlo v časopise: Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002569
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002569

Souhrn

Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XYB6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a YAKR chromosome replaced the YB6 chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/− B6 XYAKR, Wt1+/− B6 XYAKR, B6 XYPOS, and B6 XYAKR fetuses. We propose that Wt1B6 and Sf1B6 are hypomorphic alleles of testis-determining pathway genes and that Wnt4B6 is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1B6 and/or Sf1B6 alleles that compromise testis differentiation and a Wnt4B6 allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a “weak” Sry allele, such as the one on the YPOS chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal.


Zdroje

1. AchermannJCItoMHindmarshPCJamesonJL 1999 A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 22 125 126

2. CorreaRVDomeniceSBinghamNCBillerbeckAERaineyWE 2004 A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. J Clin Endocrinol Metab 89 1767 1772

3. MalletDBretonesPMichel-CalemardLDijoudFDavidM 2004 Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. J Clin Endocrinol Metab 89 4829 4832

4. LourencoDBraunerRLinLDe PerdigoAWeryhaG 2009 Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 360 1200 1210

5. PhilibertPZenatyDLinLSoskinSAudranF 2007 Mutational analysis of steroidogenic factor 1 (NR5a1) in 24 boys with bilateral anorchia: a French collaborative study. Hum Reprod 22 3255 3261

6. LinLPhilibertPFerraz-de-SouzaBKelbermanDHomfrayT 2007 Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function. J Clin Endocrinol Metab 92 991 999

7. PelletierJBrueningWKashtanCEMauerSMManivelJC 1991 Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67 437 447

8. PelletierJBrueningWLiFPHaberDAGlaserT 1991 WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 353 431 434

9. PatekCELittleMHFlemingSMilesCCharlieuJP 1999 A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc Natl Acad Sci U S A 96 2931 2936

10. JordanBKMohammedMChingSTDelotEChenXN 2001 Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet 68 1102 1109

11. JagerRJHarleyVRPfeifferRAGoodfellowPNSchererG 1992 A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet 90 350 355

12. VilainEMcElreaveyKJaubertFRaymondJPRichaudF 1992 Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet 50 1008 1011

13. JordanBKShenJHOlasoRIngrahamHAVilainE 2003 Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci U S A 100 10866 10871

14. KreidbergJASariolaHLoringJMMaedaMPelletierJ 1993 WT-1 is required for early kidney development. Cell 74 679 691

15. ShinodaKLeiHYoshiiHNomuraMNaganoM 1995 Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204 22 29

16. LuoXIkedaYParkerKL 1994 A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77 481 490

17. SadovskyYCrawfordPAWoodsonKGPolishJAClementsMA 1995 Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A 92 10939 10943

18. VeitiaRASalas-CortesLOttolenghiCPailhouxECotinotC 2001 Testis determination in mammals: more questions than answers. Mol Cell Endocrinol 179 3 16

19. EicherEMWashburnLLWhitneyJBIIIMorrowKE 1982 Mus poschiavinus Y chromosome in the C57BL/6J murine genome causes sex reversal. Science 217 535 537

20. WashburnLLEicherEM 1983 Sex reversal in XY mice caused by dominant mutation on chromosome 17. Nature 303 338 340

21. NagamineCMTaketoTKooGC 1987 Studies on the genetics of tda-1 XY sex reversal in the mouse. Differentiation 33 223 231

22. BoumaGJAlbrechtKHWashburnLLRecknagelAKChurchillGA 2005 Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells. Development 132 3045 3054

23. BoumaGJWashburnLLAlbrechtKHEicherEM 2007 Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc Natl Acad Sci U S A 104 14994 14999

24. EicherEMWashburnLLSchorkNJLeeBKShownEP 1996 Sex-determining genes on mouse autosomes identified by linkage analysis of C57BL/6J-YPOS sex reversal. Nat Genet 14 206 209

25. EicherEMWashburnLL 1986 Genetic control of primary sex determination in mice. Annu Rev Genet 20 327 360

26. EicherEM 1994 Sex and trinucleotide repeats. Nat Genet 6 221 223

27. WhitneyJBMillsTMLewisRWWartellRAbneyTO 2000 A single genetic determinant that prevents sex reversal in C57BL-YPOS congenic mice. Biochem Genet 38 119 137

28. WashburnLLAlbrechtKHEicherEM 2001 C57BL/6J-T-associated sex reversal in mice is caused by reduced expression of a Mus domesticus Sry allele. Genetics 158 1675 1681

29. AlbrechtKHYoungMWashburnLLEicherEM 2003 Sry expression level and protein isoform differences play a role in abnormal testis development in C57BL/6J mice carrying certain Sry alleles. Genetics 164 277 288

30. WilhelmDEnglertC 2002 The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev 16 1839 1851

31. IkedaYLalaDSLuoXKimEMoisanM-P 1993 Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol 7 852 860

32. LittleMHolmesGWalshP 1999 WT1: what has the last decade told us? Bioessays 21 191 202

33. ReddyJCLichtJD 1996 The WT1 Wilms' tumor suppressor gene: How much do we really know? Biochim Biophys Acta 1287 1 28

34. VainioSHeikkilaMKispertAChinNMcMahonAP 1999 Female development in mammals is regulated by Wnt-4 signalling. Nature 397 405 409

35. Jeays-WardKHoyleCBrennanJDandonneauMAlldusG 2003 Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 130 3663 3670

36. Jeays-WardKDandonneauMSwainA 2004 Wnt4 is required for proper male as well as female sexual development. Dev Biol 276 431 440

37. MenkeDBKoubovaJPageDC 2003 Sexual differentiation of germ cells in XX mouse gonads occurs in an anterior-to-posterior wave. Dev Biol 262 303 312

38. JorgensenJSGaoL 2005 Irx3 is differentially up-regulated in female gonads during sex determination. Gene Expr Patterns 5 756 762

39. CarlisleCWinkingHWeichenhanDNagamineCM 1996 Absence of correlation between Sry polymorphisms and XY sex reversal caused by the M. m. domesticus Y chromosome. Genomics 33 32 45

40. NagamineCMCarlisleC 1996 The dominant white spotting oncogene allele KitW-42J exacerbates XYDOM sex reversal. Development 122 3597 3605

41. FrigeriCTsaoJCordovaMSchimmerBP 2002 A polymorphic form of steroidogenic factor-1 is associated with adrenocorticotropin resistance in y1 mouse adrenocortical tumor cell mutants. Endocrinology 143 4031 4037

42. HammesAGuoJ-KLutschGLehesteJ-RLandrockD 2001 Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106 319 329

43. KlamtBKoziellAPoulatFWieackerPScamblerP 1998 Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/−KTS splice isoforms. Hum Mol Genet 7 709 714

44. BoumaGJHartGTWashburnLLRecknagelAKEicherEM 2004 Using real time RT-PCR analysis to determine multiple gene expression patterns during XX and XY mouse fetal gonad development. Gene Expr Patterns 5 141 149

45. NefSSchaadOStallingsNRCederrothCRPitettiJL 2005 Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Dev Biol 287 361 377

46. LeeHJPazinDEKahlonRSCorreaSMAlbrechtKH 2009 Novel markers of early ovarian pre-granulosa cells are expressed in an Sry-like pattern. Dev Dyn 238 812 825

47. HatanoOTakakusuANomuraMMorohashiK 1996 Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1 663 671

48. HeikkilaMPeltoketoHLeppaluotoJIlvesMVuolteenahoO 2002 Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143 4358 4365

49. ValPMartinez-BarberaJPSwainA 2007 Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development 134 2349 2358

50. LeeCHTaketoT 2001 Low levels of Sry transcripts cannot be the sole cause of B6-Y(TIR) sex reversal. Genesis 30 7 11

51. GregoireEPLaveryRChassotAAAkiyamaHTreierM Transient development of ovotestes in XX Sox9 transgenic mice. Dev Biol 349 65 77

52. BradfordSTWilhelmDBandieraRVidalVSchedlA 2009 A cell-autonomous role for WT1 in regulating Sry in vivo. Hum Mol Genet 18 3429 3438

53. MungerSCAylorDLSyedHAMagwenePMThreadgillDW 2009 Elucidation of the transcription network governing mammalian sex determination by exploiting strain-specific susceptibility to sex reversal. Genes Dev 23 2521 2536

54. ChassotAARancFGregoireEPRoepers-GajadienHLTaketoMM 2008 Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet 17 1264 1277

55. TomizukaKHorikoshiKKitadaRSugawaraYIbaY 2008 R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum Mol Genet 17 1278 1291

56. EicherEMWashburnLL 1983 Inherited sex reversal in mice: Identification of a new primary sex-determining gene. J Exp Zool 228 297 304

57. WashburnLLEicherEM 1989 Normal testis determination in the mouse depends on genetic interaction of a locus on chromosome 17 and the Y chromosome. Genetics 123 173 179

58. StarkKVainioSVassilevaGMcMahonAP 1994 Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372 679 683

59. CapelBAlbrechtKHWashburnLLEicherEM 1999 Migration of mesonephric cells into the mammalian gonad depends on Sry. Mech Dev 84 127 131

60. HackerACapelBGoodfellowPLovell-BadgeR 1995 Expression of Sry, the mouse sex determining gene. Development 121 1603 1614

61. KaufmanM 2003 The Atlas of Mouse Development; KaufmanM London Academic Press

62. EicherEMBeamerWGWashburnLLWhittenWK 1980 A cytogenetic investigation of inherited true hermaphroditism in BALB/cWt mice. Cytogenet Cell Genet 28 104 115

63. EicherEMWashburnLL 2001 Does one gene determine whether a C57BL/6J-YPOS mouse will develop as a female or as an hermaphrodite? J Exp Zool 290 322 326

64. AlbrechtKHEicherEM 2001 Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev Biol 240 92 107

65. WilkinsonDG 1992 Whole mount in situ hybridization of vertebrate embryos. WilkinsonDG In situ hybridization: A Practical Approach. 2nd ed Oxford IRL Press 75 83

66. LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25 402 408

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