The Nucleoside Diphosphate Kinase Gene Acts as Quantitative Trait Locus Promoting Non-Mendelian Inheritance

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The t-haplotype, a variant form of the t-complex region on mouse chromosome 17, acts as selfish genetic element and is transmitted at high frequencies (>95%) from heterozygous (t/+) males to their offspring. This phenotype is termed transmission ratio distortion (TRD) and is caused by the interaction of the t-complex responder (Tcr) with several quantitative trait loci (QTL), the t-complex distorters (Tcd1 to Tcd4), all located within the t-haplotype region. Current data suggest that the distorters collectively impair motility of all sperm derived from t/+ males; t-sperm is rescued by the responder, whereas +-sperm remains partially dysfunctional. Recently we have identified two distorters as regulators of RHO small G proteins. Here we show that the nucleoside diphosphate kinase gene Nme3 acts as a QTL on TRD. Reduction of the Nme3 dosage by gene targeting of the wild-type allele enhanced the transmission rate of the t-haplotype and phenocopied distorter function. Genetic and biochemical analysis showed that the t-allele of Nme3 harbors a mutation (P89S) that compromises enzymatic activity of the protein and genetically acts as a hypomorph. Transgenic overexpression of the Nme3 t-allele reduced t-haplotype transmission, proving it to be a distorter. We propose that the NME3 protein interacts with RHO signaling cascades to impair sperm motility through hyperactivation of SMOK, the wild-type form of the responder. This deleterious effect of the distorters is counter-balanced by the responder, SMOK^Tcr, a dominant-negative protein kinase exclusively expressed in t-sperm, thus permitting selfish behaviour and preferential transmission of the t-haplotype. In addition, the previously reported association of NME family members with RHO signaling in somatic cell motility and metastasis, in conjunction with our data involving RHO signaling in sperm motility, suggests a functional conservation between mechanisms for motility control in somatic cells and spermatozoa.

Vyšlo v časopise: The Nucleoside Diphosphate Kinase Gene Acts as Quantitative Trait Locus Promoting Non-Mendelian Inheritance. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002567
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002567

Souhrn

Zdroje

1. SilverLM 1993 The peculiar journey of a selfish chromosome: mouse t haplotypes and meiotic drive. Trends Genet 9 250 254

2. SchimentiJ 2000 Segregation distortion of mouse t haplotypes the molecular basis emerges. Trends Genet 16 240 243

3. LyonMF 2003 Transmission ratio distortion in mice. Annu Rev Genet 37 393 408

4. ChesleyPDunnLC 1936 The Inheritance of Taillessness (Anury) in the House Mouse. Genetics 21 525 536

5. KatzDFEricksonRPNathansonM 1979 Beat frequency is bimodally distributed in spermatozoa from T/t12 mice. J Exp Zool 210 529 535

6. Olds-ClarkePJohnsonLR 1993 t haplotypes in the mouse compromise sperm flagellar function. Dev Biol 155 14 25

7. Olds-ClarkePPeitzB 1985 Fertility of sperm from t/+ mice: evidence that +-bearing sperm are dysfunctional. Genet Res 47 49 52

8. HerrmannBGKoschorzBWertzKMcLaughlinKJKispertA 1999 A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. Nature 402 141 146

9. VeronNBauerHWeisseAYLuderGWerberM 2009 Retention of gene products in syncytial spermatids promotes non-Mendelian inheritance as revealed by the t complex responder. Genes Dev 23 2705 2710

10. BauerHWillertJKoschorzBHerrmannBG 2005 The t complex-encoded GTPase-activating protein Tagap1 acts as a transmission ratio distorter in mice. Nat Genet 37 969 973

11. BauerHVeronNWillertJHerrmannBG 2007 The t-complex-encoded guanine nucleotide exchange factor Fgd2 reveals that two opposing signaling pathways promote transmission ratio distortion in the mouse. Genes Dev 21 143 147

12. HuberCMartenssonABokochGMNemazeeDGavinAL 2008 FGD2, a CDC42-specific exchange factor expressed by antigen-presenting cells, localizes to early endosomes and active membrane ruffles. J Biol Chem 283 34002 34012

13. ErentMGoninPCherfilsJTissierPRaschellaG 2001 Structural and catalytic properties and homology modelling of the human nucleoside diphosphate kinase C, product of the DRnm23 gene. Eur J Biochem 268 1972 1981

14. BoissanMDabernatSPeuchantESchlattnerULascuI 2009 The mammalian Nm23/NDPK family: from metastasis control to cilia movement. Mol Cell Biochem

15. ChalmelFRollandADNiederhauser-WiederkehrCChungSSDemouginP 2007 The conserved transcriptome in human and rodent male gametogenesis. Proc Natl Acad Sci U S A 104 8346 8351

16. LascuIChaffotteALimbourg-BouchonBVeronM 1992 A Pro/Ser substitution in nucleoside diphosphate kinase of Drosophila melanogaster (mutation killer of prune) affects stability but not catalytic efficiency of the enzyme. J Biol Chem 267 12775 12781

17. TimmonsLXuJHerspergerGDengXFShearnA 1995 Point mutations in awdKpn which revert the prune/Killer of prune lethal interaction affect conserved residues that are involved in nucleoside diphosphate kinase substrate binding and catalysis. J Biol Chem 270 23021 23030

18. LyonMF 1984 Transmission ratio distortion in mouse t-haplotypes is due to multiple distorter genes acting on a responder locus. Cell 37 621 628

19. BucanMHerrmannBGFrischaufAMBautchVLBodeV 1987 Deletion and duplication of DNA sequences is associated with the embryonic lethal phenotype of the t9 complementation group of the mouse t complex. Genes Dev 1 376 385

20. HowardTBaloghROverbeekPBernsteinKE 1993 Sperm-specific expression of angiotensin-converting enzyme (ACE) is mediated by a 91-base-pair promoter containing a CRE-like element. Mol Cell Biol 13 18 27

21. MurakamiMMenesesPIKnightJSLanKKaulR 2008 Nm23-H1 modulates the activity of the guanine exchange factor Dbl-1. Int J Cancer 123 500 510

22. MurakamiMMenesesPILanKRobertsonES 2008 The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration. Cancer Biol Ther 7 677 688

23. OtsukiYTanakaMYoshiiSKawazoeNNakayaK 2001 Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci U S A 98 4385 4390

24. LyonMF 1992 Deletion of mouse t-complex distorter-1 produces an effect like that of the t-form of the distorter. Genet Res 59 27 33

25. LyonMF 2005 Elucidating mouse transmission ratio distortion. Nat Genet 37 924 925

26. MunierASerresCKannMLBoissanMLesaffreC 2003 Nm23/NDP kinases in human male germ cells: role in spermiogenesis and sperm motility? Exp Cell Res 289 295 306

27. GummereGRMcCormickPJBennettD 1986 The influence of genetic background and the homologous chromosome 17 on t-haplotype transmission ratio distortion in mice. Genetics 114 235 245

28. McDermottWGBoissanMLacombeMLSteegPSHorakCE 2008 Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth. Clin Exp Metastasis 25 131 138

29. CarinciFArcelliDLo MuzioLFranciosoFValentiniD 2007 Molecular classification of nodal metastasis in primary larynx squamous cell carcinoma. Transl Res 150 233 245

30. BrentAESchweitzerRTabinCJ 2003 A somitic compartment of tendon progenitors. Cell 113 235 248

31. SwiatekPJGridleyT 1993 Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev 7 2071 2084

32. Ramirez-SolisRDavisACBradleyA 1993 Gene targeting in embryonic stem cells. Methods Enzymol 225 855 878

33. ChungJHWhiteleyMFelsenfeldG 1993 A 5′ element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell 74 505 514

34. YanoAUmedaMUchimiyaH 1995 Expression of functional proteins of cDNA encoding rice nucleoside diphosphate kinase (NDK) in Escherichia coli and organ-related alteration of NDK activities during rice seed germination (Oryza sativa L.). Plant Mol Biol 27 1053 1058