The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-Mendelian inheritance.
The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-Mendelian inheritance.
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DOI：
10.1371/journal.pgen.1002567
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Herrmann BG
中科院分区：
文献类型：
--
作者：
Bauer H;Schindler S;Charron Y;Willert J;Kusecek B;Herrmann BG
T-单倍型是小鼠17号染色体上t-复合体区域的一种变异形式，作为自私的遗传元件，在杂合子(t/+)雄性之间以高频率(>；95%)传播给他们的后代。这种表型被称为传递比失真(TRD)，它是由t-复合体响应器(TCR)与多个数量性状基因座(QTL)、t-复合体畸变子(Tcd1至Tcd4)相互作用引起的，它们都位于t-单倍型区域内。目前的数据表明，畸变者共同削弱了来自t/+男性的所有精子的活力；t-精子被应答者拯救，而+-精子仍然部分功能失调。最近，我们发现了两个Rho小G蛋白的调节子。在这里，我们证明了核苷二磷酸激酶基因Nme3是TRD上的一个QTL。通过野生型等位基因打靶来减少Nme3的剂量，提高了t单倍型和表型扭曲功能的传递率。遗传和生化分析表明，Nme3的t等位基因含有一个突变(P89S)，该突变会影响蛋白质的酶活性，并在遗传上表现为低晶型。Nme3t等位基因的转基因过表达减少了t单倍型的传播，证明它是一种扭曲。我们认为，NME3蛋白与Rho信号通路相互作用，通过过度激活Smok(野生型反应者)来损害精子的活力。这种扭曲的有害影响被反应因子SMOKTcr抵消，SMOKTcr是一种显性负蛋白激酶，仅在t-精子中表达，从而允许自私行为和t-单倍型的优先传递。此外，先前报道的NME家族成员与Rho信号在体细胞运动和转移中的关联，结合我们涉及Rho信号在精子运动中的数据，表明体细胞和精子运动控制机制之间的功能保守。自私的遗传因素促进了自身的繁殖，从而违反了孟德尔定律，在科学界和公众中引起了极大的关注。一般说来，它们特殊行为背后的分子原理还没有得到很好的理解。一个值得注意的例外是小鼠的t-单倍型，它于1936年被发现，自那以来一直是哺乳动物非孟德尔遗传的范例。最近，我们揭示了该遗传区域内几个元件的分子性质，包括t-复合体响应器和两个t-复合体畸变子，它们相互作用，促进t-单倍型从男性(携带该变异基因区域)向其后代的高传递率。在这里，我们证明了核苷二磷酸激酶基因Nme3作为扭曲因子，从而导致了t-单倍型的高传递率。我们发现Nme3作为数量性状基因与Rho信号级联相互作用，参与精子的运动控制。由于人类NME家族成员与体细胞运动(也受Rho信号控制)和癌细胞转移有关，我们提出了体细胞和精子细胞运动控制之间的功能保守。
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, SMOKTcr, 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. Selfish genetic elements, which promote their own propagation and thereby violate Mendel's laws, have attracted much attention within the scientific community and by the public. The molecular principles underlying their exceptional behaviour are, in general, not well understood. A notable exception is the t-haplotype of the mouse, which was discovered in 1936 and has since been a paradigm for non-Mendelian inheritance in mammals. Recently we have revealed the molecular nature of several elements within this genetic region, including the t-complex responder and two t-complex distorters that interact to promote the high transmission rate of the t-haplotype from males (which carry this variant genetic region) to their offspring. Here we show that the nucleoside diphosphate kinase gene, Nme3, acts as distorter and thus contributes to the high transmission rate of the t-haplotype. We show that Nme3 acts as quantitative trait locus and interacts with RHO signaling cascades involved in sperm motility control. Since human NME family members have been associated with somatic cell motility (which is also controlled by RHO signalling) and cancer cell metastasis, we propose a functional conservation between motility control in somatic and sperm cells.
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影响因子：
3.6
作者：
Murakami, Masanao;Meneses, Patricio I.;Robertson, Erle S.
通讯作者：
Robertson, Erle S.
DOI：
10.1073/pnas.071411598
发表时间：
2001-04-10
影响因子：
11.1
作者：
Otsuki, Y;Tanaka, M;Sugimura, H
通讯作者：
Sugimura, H
影响因子：
7.8
作者：
Carinci, Francesco;Arcelli, Diego;Tete, Stefano
通讯作者：
Tete, Stefano
影响因子：
10.5
作者：
BUCAN, M;HERRMANN, BG;LEHRACH, H
通讯作者：
LEHRACH, H
DOI：
10.1046/j.1432-1327.2001.2076.doc.x
发表时间：
2001-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Erent, M;Gonin, P;Lascu, I
通讯作者：
Lascu, I