No abstract

In meiosis I, exchanges provide a connection between homologous chromosome pairs that facilitates their proper attachment to the meiotic spindle. In many eukaryotes, homologous chromosomes that fail to become linked by exchanges exhibit elevated levels of meiotic errors, but they do not segregate randomly, demonstrating that mechanisms beyond exchange can promote proper meiosis I segregation. The experiments described here demonstrate the existence of a meiotic centromere pairing mechanism in budding yeast. This centromere pairing mediates the meiosis I bipolar spindle attachment of nonexchange chromosome pairs and likely plays the same role for all homologous chromosome pairs.Supplemental material is available at http://www.genesdev.org. Exchanges (crossovers), which occur between homologous chromosomes in meiosis I, are critical for the production of viable gametes because they link the homologs together (Bascom-Slack et al. 1997). This linkage allows the homologs to remain joined during the process of microtubule attachment and enables the homologous pair to achieve a bipolar spindle attachment (the centromeres of the homologs attached to microtubules from opposite spindle poles), analogous to sister chromatids in mitotic cells. The importance of recombination in ensuring high-fidelity chromosome segregation might suggest that a pair of nonexchange chromosomes, in an otherwise normal meiosis I, would segregate randomly. However, this is not always the case (Wolf 1994). In several organisms, it has been shown that a single nonexchange pair of chromosomes will be segregated properly in most meioses. Most notably, female Drosophila melanogaster use the pairing of centric heterochromatin to mediate the segregation of the nonexchange fourth chromosome pair (Dernburg et al. 1996;Karpen et al. 1996). In the budding yeast Saccharomyces cerevisiae, a single chromosome pair without an exchange segregates properly in ∼90% of meioses (Dawson et al. 1986;Mann and Davis 1986;Guacci and Kaback 1991;Ross et al. 1996). These examples of nonexchange segregation demonstrate that there are mechanisms, other than exchange, that contribute to the ability of a chromosome pair to assume a bipolar spindle attachment in meiosis I. The nature of these mechanisms remains largely mysterious. In yeast, nonexchange segregation is not based on DNA sequence homology; numerous studies have shown that nonexchange chromosome pairs that are nonhomologous, even at their centromeres, segregate with the same fidelity (90%) as nonexchange pairs that are perfectly homologous (Ross et al. 1996).The experiments described here explore the mechanisms, beyond exchange, that contribute to meiotic segregation fidelity in S. cerevisiae. For these experiments we have constructed a novel yeast strain that has one obligate nonexchange chromosome pair. This strain was created by replacing one copy of S. cerevisiae Chromosome V with Chromosome V from Saccharomyces carlsbergensis, which provides full function in haploid S. cerevisiae. These "homeologous" chromosom...

Summary MicroRNAs (miRNAs) are small, non-coding RNAs that regulate the translation and/or the stability of their mRNA targets. Previous work showed that for most miRNA genes of C. elegans, single gene knockouts did not result in detectable mutant phenotypes [1]. This may be due, in part, to functional redundancy between miRNAs. However, in most cases, worms carrying deletions of all members of a miRNA family do not display strong mutant phenotypes [2]. They may function together with unrelated miRNAs or with non-miRNA genes in regulatory networks, possibly to ensure the robustness of developmental mechanisms. To test this, we examined worms lacking individual miRNAs in genetically sensitized backgrounds. These include genetic backgrounds with reduced processing and activity of all miRNAs or with reduced activity of a wide array of regulatory pathways [3]. Using these two approaches, mutant phenotypes were identified for 25 out of 31 miRNAs included in this analysis. Our findings describe biological roles for individual miRNAs and suggest that use of sensitized genetic backgrounds provides an efficient approach for miRNA functional analysis.

Errors in meiotic chromosome segregation are the leading cause of spontaneous abortions and birth defects. In humans, chromosomes that fail to experience crossovers (or exchanges) are error-prone, more likely than exchange chromosomes to mis-segregate in meiosis. We used a yeast model to investigate the mechanisms that partition nonexchange chromosomes. These studies showed that the spindle checkpoint genes MAD1, MAD2 and MAD3 have different roles. We identified a new meiotic role for MAD3; though dispensable for the segregation of exchange chromosomes, it is essential for the segregation of nonexchange chromosomes. This function of Mad3p could also be carried out by human BubR1. MAD1 and MAD2 act in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes, whereas MAD3 acts as a crucial meiotic timer, mediating a prophase delay in every meiosis. These findings suggest plausible models for the basis of errant meiotic segregation in humans.