Five of the nine genetically defined regions of mouse<i>t</i>haplotypes are involved in transmission ratio distortion

Silver, Lee M.; Remis, D.

doi:10.1017/s0016672300026720

Cited by 88 publications

(45 citation statements)

References 23 publications

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“…Finally and most germane to the results presented here are previous genetic studies showing a connection between TCP-1 and microtubule-related phenomenon. In the mouse, where the TCP-1 locus was first identified, mutations in the locus were always associated with transmission ratio distortions (11), perhaps indicative of microtubule abnormalities. In addition, the TCP-1 protein was shown to be expressed at high levels during spermatogenesis, a process that requires the assembly of complex macromolecular structures, including the microtubule core of the flagellum.…”

Section: Discussionmentioning

confidence: 99%

“…In mice, expression of TCP-1 increases markedly during spermatogenesis (10), a process that requires the assembly of complex macromolecular structures including the microtubule core of the flagellum. In addition, mutations within the TCP-1 locus are associated with both microtubule abnormalities and transmission ratio distortions (11). Similarly in yeast, temperaturesensitive mutations of the TCP-1 gene result in a number of alterations in microtubule mediated processes.…”

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confidence: 99%

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Molecular Chaperones and the Centrosome

Brown

Doxsey

Hong-Brown

et al. 1996

Journal of Biological Chemistry

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Molecular chaperones play an important role in facilitating the proper maturation of many newly synthesized proteins. Here we provide evidence that molecular chaperones also participate in regulating the assembly of the microtubule cytoskeleton. Via indirect immunofluorescence analysis, both hsp 73 and TCP-1 localized within the centrosome in interphase and mitotic cells. These proteins, along with the centrosome-specific protein, pericentrin, were also present within an enriched preparation of centrosomes. Because the centrosome serves as an initiation site for microtubule growth, we examined the ability of cells to regrow their microtubule network in the presence of hsp 73 or TCP-1 specific antibodies. Purified tubulin and GTP were added to cells following the depolymerization and extraction of cellular microtubules. Microtubules were observed to nucleate off the centrosome using this system, even in the presence of anti-hsp 73 antibodies. Incubation with anti-TCP-1 antibodies, however, blocked microtubule regrowth off the centrosome. Similarly, anti-TCP-1 antibodies microinjected into living cells first treated with nocodazole also inhibited the regrowth of the microtubule network following removal of the microtubule poison. Our results complement earlier genetic studies in yeast implicating a role for TCP-1 in microtubule mediated processes, and may help to explain the previously reported mitotic and meiotic abnormalities associated with TCP-1 mutations.A class of proteins, now being referred to as molecular chaperones, facilitate various aspects of protein maturation. Perhaps the best characterized molecular chaperones are members of the so-called heat shock (hsp) or stress protein family (recently reviewed in Refs. 1 and 2). In animal cells, members of the hsp 70 family (DnaK in bacteria) are distributed throughout various cellular compartments and interact with proteins being synthesized on polysomes and/or being translocated into organelles. Such an interaction with the hsp 70 proteins likely serves to stabilize and/or maintain the nascent polypeptide in a relatively unfolded state until its synthesis and/or translocation has been completed. Members of the eukaryotic hsp 60 family (GroEL in bacteria) also bind newly synthesized and unfolded polypeptides. This class of molecular chaperones, often called chaperonins, are thought to provide a shielded environment in which protein folding and/or higher ordered protein assembly takes place. Although exhibiting only weak homology with other members of the chaperonin family, a eukaryotic cytosolic chaperonin has been identified and, like other members of the chaperonin family, exists as a large (ϳ20 S) particle (3, 4).Despite structural similarities to other members of the chaperone family, the cytosolic chaperonin exhibits a number of differences as it relates to both its subunit composition, mode of regulation, and apparent substrate specificity. First, at least 8 related subunits, referred to as the TCP-1 family, appear to comprise the cytosolic chaperonin c...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Molecular Chaperones and the Centrosome

Brown

Doxsey

Hong-Brown

et al. 1996

Journal of Biological Chemistry

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“…For additional evidence that t""j contains no wild-type T66 genes, note the absence of wrild-type fragments in Figure 2A. 1984;LYON 1986;SILVER and REMIS 1987).…”

Section: Discussionmentioning

confidence: 99%

“…and the t complex responder. Tcr (LYON 1984: SILVER andREMIS 1987). Tcd-2 is located somewhere between T66C and the distal end of the t complex.…”

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confidence: 99%

Molecular cloning and genetic mapping of the t complex responder candidate gene family

1990

Trends in Genetics

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Male transmission ratio distortion (TRD) is a property of mouse t haplotypes requiring the t complex responder locus (Tcr). Tcr maps to the central region oft haplotypes, and is embedded within a series of large duplicated tracts of DNA known as "T66 elements." In previous work, a family of genes (the "T66" genes) was identified within this region that encodes male germ cell-specific transcripts. Genetic and molecular data indicate that one of these genes represents Tcr. Here, we describe the molecular cloning of the four members of the T66 gene family, the genetic mapping of these genes to three adjacent t haplotype loci, and comparative restriction enzyme analysis of the genes.The results indicate that these genes are highly similar to one another, and were created by recent, complex duplication events. This suggests that a minor alteration(s) could have been responsible for conferring "mutant" responder activity upon Tcr, while the other homologs retained "wild-type" biochemical function. In addition, we have identified and mapped three T66 genes in wild-type t complexes. They reside in two separate loci at the opposite ends of the proximal t complex inversion, and are separated by at least 3 cM. at least one recessive developmental lethal mutation, and males heterozygous for two complementing t haplotypes are sterile, these variant chromosomes propagate to high frequencies in wild mouse populations due to male transmission ratio distortion (TRD). This causes male mice heterozygous for a t haplotype and a wild-type form of the t complex ( + / t ) to transmit the t chromosome to nearly all of their offspring.TRD is believed to occur through the action of at least four trans-acting t complex distorter (Tcd) loci upon a t complex responder (Tcr)

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“…1A;Lyon 2003). However, rare recombinants have been isolated and utilized to identify and map four Distorter loci (t-complex distorters 1-4, Tcd1-4) and the single Responder (t-complex responder, Tcr) to chromosomal subregions of several megabases (Lyon 1984;Silver and Remis 1987). Genetic data demonstrated that Tcd loci act additively in enhancing the transmission rate of Tcr.…”

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confidence: 99%

The t-complex-encoded guanine nucleotide exchange factor Fgd2 reveals that two opposing signaling pathways promote transmission ratio distortion in the mouse

Bauer¹,

Véron²,

Willert³

et al. 2007

Genes Dev.

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Transmission ratio distortion (TRD), the preferential inheritance of the t haplotype from t/+ males, is caused by the cooperative effect of four t-complex distorters (Tcd1-4) and the single t-complex responder (Tcr) on sperm motility. Here we show that Fgd2, encoding a Rho guanine nucleotide exchange factor, maps to the Tcd2 region. The t haplotype is a variant form of the proximal third of mouse chromosome 17, which was isolated from wild mouse populations (Schimenti 2000;Lyon 2003). Heterozygous t/+ males preferentially (up to 99%) transmit the t chromosome to their offspring. Meiotic recombination between t-haplotype and wild-type chromosomes is strongly suppressed due to four large inversions, ensuring cotransmission of all factors involved in transmission ratio distortion (TRD) ( Fig. 1A; Lyon 2003). However, rare recombinants have been isolated and utilized to identify and map four Distorter loci (t-complex distorters 1-4, Tcd1-4) and the single Responder (t-complex responder, Tcr) to chromosomal subregions of several megabases (Lyon 1984;Silver and Remis 1987). Genetic data demonstrated that Tcd loci act additively in enhancing the transmission rate of Tcr. It was suggested that Distorter genes have a harmful effect on sperm function, brought about by an action on the Responder, and that the wild-type allele of the Responder is more sensitive than the t form (Lyon 1986). Motility tests showed that part of the sperm derived from t/+ males displays altered beat frequency and impaired forward movement, while sperm from males carrying two t haplotypes becomes immotile quickly (Katz et al. 1979;Olds-Clarke and Johnson 1993). These and other data have led to the conclusion that Tcds compromise the motility of all sperm, while Tcr specifically rescues sperm carrying this gene, giving t sperm an advantage in reaching the oocytes.A molecular dissection of the TRD phenomenon became possible through cloning of the Responder gene Smok1Tcr (Herrmann et al. 1999), which encodes a dominant-negative form of the protein kinase Smok1. The biochemical function of Tcr suggested that Tcd genes encode signaling molecules acting upstream of Smok1. In accordance with this model, we demonstrated that Tcd1a encodes the GTPase-activating protein Tagap1, a control factor of Rho G proteins (Bauer et al. 2005). This result prompted us to search the distal t-haplotype region for Distorter candidates, using the following criteria: The gene must (1) be located in the genomic interval comprising Tcd2, (2) encode a protein involved in signaling, (3) be expressed in testis, and (4) show alterations in the t haplotype as compared with the wild-type allele.

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Five of the nine genetically defined regions of mousethaplotypes are involved in transmission ratio distortion

Cited by 88 publications

References 23 publications

Molecular Chaperones and the Centrosome

Molecular Chaperones and the Centrosome

Molecular cloning and genetic mapping of the t complex responder candidate gene family

The t-complex-encoded guanine nucleotide exchange factor Fgd2 reveals that two opposing signaling pathways promote transmission ratio distortion in the mouse

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