title: The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-Mendelian inheritance.
abstract: 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.
authors.affiliation: Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany. herrmann@molgen.mpg.de
authors.forename: Hermann
authors.initials: H
authors.lastname: Bauer
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schindler
authors.forename: Yves
authors.initials: Y
authors.lastname: Charron
authors.forename: Jürgen
authors.initials: J
authors.lastname: Willert
authors.forename: Barica
authors.initials: B
authors.lastname: Kusecek
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D040941:Heredity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics; D013081:Sperm Motility / Q000235:genetics*; D013094:Spermatozoa / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D056427:t-Complex Genome Region / Q000235:genetics*
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D011494:Protein Kinases; C403405:Smok1 protein, mouse; C517944:Nme3 protein, mouse; D020741:rho GTP-Binding Proteins