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Meiosis: A Special Type of Cell Division

In nearly all eukaryotes, meiosis generates haploid germ cells (eggs and sperm), which can then fuse to generate a diploid zygote (Figure 21-34). During meiosis, a single round of DNA replication is followed by two cycles of cell division, termed meiosis I and meiosis II. Crossing over of chro-matids, visible in the first meiotic metaphase, produces recombination between parental chromosomes. This increases the genetic diversity among the individuals of a species. During meiosis I, both chromatids of each homologous chromosome segregate together to opposite spindle poles, so that each of the resulting daughter cells contains one homologous chromosome consisting of two chromatids. During meiosis II, which resembles mitosis, the chromatids of one chromosome segregate to opposite spindle poles, generating haploid germ cells. Meiosis generates four haploid germ cells from one diploid premeiotic cell.

Repression of G1 Cyclins and Meiosis-Specific Ime2 Prevents DNA Replication in Meiosis II

In sS. cerevisiae and ,S. pombe, depletion of nitrogen and carbon sources induces diploid cells to undergo meiosis, yielding haploid spores (see Figure 1-5). This process is analogous to

► FIGURE 21-34 Meiosis. Premeiotic cells have two copies of each chromosome (2n), one derived from the paternal parent and one from the maternal parent. For simplicity, the paternal and maternal homologs of only one chromosome are diagrammed. Step 1 : All chromosomes are replicated during the S phase before the first meiotic division, giving a 4n chromosomal complement. Cohesin complexes (not shown) link the sister chromatids composing each replicated chromosome along their full lengths. Step 2| : As chromosomes condense during the first meiotic prophase, replicated homologs become paired as the result of at least one crossover event between a paternal and a maternal chromatid. This pairing of replicated homologous chromosomes is called synapsis. At metaphase, shown here, both chromatids of one chromosome associate with microtubules emanating from one spindle pole, but each member of a homologous chromosome pair associates with microtubules emanating from opposite poles. Step 3 : During anaphase of meiosis I, the homologous chromosomes, each consisting of two chromatids, are pulled to opposite spindle poles. Step 4| : Cytokinesis yields the two daughter cells (now 2n), which enter meiosis II without undergoing DNA replication. At metaphase of meiosis II, shown here, the chromatids composing each replicated chromosome associate with spindle microtubules from opposite spindle poles, as they do in mitosis. Steps 5 and 6: Segregation of chromatids to opposite spindle poles during the second meiotic anaphase followed by cytokinesis generates haploid germ cells (1 n) containing one copy of each chromosome (referred to as chromatids earlier).

the formation of germ cells in higher eukaryotes. Multiple yeast mutants that cannot form spores have been isolated, and the wild-type proteins encoded by these genes have been analyzed. These studies have identified specialized cell-cycle proteins that are required for meiosis.

Under starvation conditions, expression of G1 cyclins (Cln1/2/3) in cerevisiae is repressed, blocking the normal progression of G1 in cells as they complete mitosis. Instead, a set of early meiotic proteins are induced. Among these is Ime2, a protein kinase that performs the essential G1 cyclin-CDK function of phosphorylating the S-phase inhibitor Sic1, leading to release of active S-phase cyclin-CDK complexes and the onset of DNA replication in meiosis I (see Figure 21-34, step 1). The absence of Ime2 expression during meio-sis II and the continued repression of Cln expression account for the failure to replicate DNA during the second meiotic division (steps 5 and 6).

Crossing Over and Meiosis-Specific Rec8 Are Necessary for Specialized Chromosome Segregation in Meiosis I

Recall that in mitosis, sister chromatids replicated during the S phase are initially linked by cohesin complexes at multiple positions along their full length (see Figure 21-19, left). As chromosomes condense, cohesin complexes become restricted to the region of the centromere, and at metaphase, the sister chromatids composing each (replicated) chromosome associate with microtubules emanating from opposite spindle poles. Although motor proteins pull sister chro-matids toward opposite spindle poles, their movement initially is resisted by the cohesin complexes linking them at the centromere. The subsequent separase-catalyzed cleavage of the Scc1 cohesin subunit permits movement of the chromatids toward the spindle poles to begin, heralding the onset of anaphase (Figure 21-35a; see also Figure 21-19, right).

In metaphase of meiosis I, both sister chromatids in one (replicated) chromosome associate with microtubules emanating from the same spindle pole, rather than from opposite poles as they do in mitosis. Two physical links between homologous chromosomes are thought to resist the pulling force of the spindle until anaphase: (a) crossing over between chromatids, one from each pair of homologous chromosomes, and (b) cohesin cross-links between chromatids distal to the crossover point.

Evidence for the role of crossing over in meiosis in sS. cerevisiae comes from the observation that when recombination is blocked by mutations in proteins essential for the process, chromosomes segregate randomly during meiosis I; that is, homologous chromosomes do not necessarily segregate to opposite spindle poles. Such segregation to opposite spindle poles normally occurs because both chromatids of homologous chromosome pairs associate with spindle fibers emanating from opposite spindle

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▲ FIGURE 21-35 Cohesin function during mitosis and meiosis. (a) During mitosis, sister chromatids generated by DNA replication in the S phase are initially associated by cohesin complexes along the full length of the chromatids. During chromosome condensation, cohesin complexes (yellow) become restricted to the region of the centromere at metaphase, as depicted here. Once separase cleaves the Scc1 cohesin subunit, sister chromatids can separate, marking the onset of anaphase (see Figure 21-19). (b) In metaphase of meiosis I, crossing over between maternal and paternal chromatids produces synapsis of homologous parental chromosomes. The chromatids of each replicated chromosome are cross-linked by cohesin complexes along their full length. Rec8, a meiosis-specific homolog of Scc1, is cleaved in chromosome arms but not in the centromere, allowing homologous chromosome pairs to segregate to daughter cells. Centromeric Rec8 is cleaved during meiosis II, allowing individual chromatids to segregate to daughter cells. [Modified from F Uhlmann, 2001, Curr. Opin. Cell Biol. 13:754.]

poles (see Figure 21-34, step [3). This in turn requires that homologous chromosomes pair during meiosis I, a process called synapsis that can be visualized microscopically in eukaryotes with large chromosomes. Consequently, the finding that mutations that block recombination also block proper segregation in meiosis I implies that recombination is required for synapsis in ,S. cerevisiae. In higher eukaryotes, processes in addition to recombination and chromatid linking through cohesin complexes contribute to synapsis in meiosis I.

During meiosis I, the cohesin cross-links between chromosome arms are cleaved by separase, allowing the homologous chromosomes to separate, but cohesin complexes at the centromere remain linked (Figure 21-35b, top). The maintenance of centromeric cohesion during meiosis I is necessary for the proper segregation of chromatids during meiosis II. Recent studies with a ,S. pombe mutant have shown that a specialized cohesin subunit, Rec8, maintains centromeric cohesion between sister chromatids during meiosis I. Expressed only during meiosis, Rec8 is homologous to Scc1, the cohesin subunit that forms the actual bridge between sister chromatids in mitosis (see Figure 21-19). Immunolocalization experiments in S. pombe have revealed that during early anaphase of meiosis I, Rec8 is lost from chromosome arms but is retained at centromeres. However, during early anaphase of meiosis II, centromeric Rec8 is degraded by separase, so the chromatids can segregate, as they do in mitosis (Figure 21-35b, bottom). A specific protein expressed during meiosis I, but not during meiosis II, protects centromeric Rec8 from separase cleavage in meiosis I.

sS. cerevisiae Rec8 has been shown to localize and function similarly to ,S. pombe Rec8. Homologs of Rec8 also have been identified in higher organisms, and RNA interference (RNAi) experiments in C. elegans (Chapter 9) indicate that the Rec8 homolog in that organism has a similar function. Recent micromanipulation experiments during grasshopper sper-matogenesis support the hypothesis that kinetochore-bound proteins protect centromeric Rec8 from cleavage during meiosis I but not during meiosis II and also direct kinetochore attachment to microtubules emanating from the correct spindle pole (Figure 21-36). Thus crossing over, Rec8, and special kinetochore-associated proteins appear to function in meiosis in all eukaryotes.

Recent DNA microarray analyses in S. cerevisiae have revealed other proteins that are required for meiosis. As discussed in other chapters, researchers can monitor transcription of thousands of genes, indeed entire genomes, with DNA microarrays (see Figure 9-35). One of the multiple genes found to be expressed in ,S. cerevisiae cells during meiosis but not during mitosis is MAM1, which encodes a protein called monopolin. Subsequent gene-specific mutagenesis studies revealed that deletion of MAM1 causes sister chromatids in metaphase of meiosis I to associate with the first meiotic spindle as though they were mitotic chromatids or chromatids in meiosis II. That is, kinetochores of the sister chromatids composing a single (replicated) chromosome attached to microtubules emanating from opposite spindle poles rather than from the same spindle pole. This result indicates that monopolin is required for formation of a specialized kinetochore in meiosis I responsible for the unique co-orientation of sister chromatids of synapsed homologous chromosomes in the first meiotic division.

▲ EXPERIMENTAL FIGURE 21-36 Anaphase movements and cohesion of meiotic chromosomes are determined by proteins associated with the chromosomes. Grasshopper spermatocytes in meiosis I and II were fused so that both types of spindles with their associated chromosomes were present in a single fused cell. Then a micromanipulation needle was used to move some meiosis I chromosomes (blue) and meiosis II chromosomes (red) from one spindle to another; other chromosomes were left attached to their normal spindles. After 70 minutes, both spindles with their attached chromosomes had completed anaphase movements. The synapsed meiosis I chromosomes (blue) separated normally (i.e., one homologous

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