Segregation of homologous chromosomes during meiosis depends on linkages (chiasmata) created by crossovers and on selective release of a subset of sister chromatid cohesion at anaphase I. DuringCaenorhabditis elegans meiosis, each chromosome pair forms a single crossover, and the position of this event determines which chromosomal regions will undergo cohesion release at anaphase I. Here we provide insight into the basis of this coupling by uncovering a large-scale regional change in chromosome axis composition that is triggered by crossovers. We show that axial element components HTP-1 and HTP-2 are removed during late pachytene, in a crossover-dependent manner, from the regions that will later be targeted for anaphase I cohesion release. We demonstrate correspondence in position and number between chiasmata and HTP-1/2-depleted regions and provide evidence that HTP-1/2 depletion boundaries mark crossover sites. In htp-1 mutants, diakinesis bivalents lack normal asymmetrical features, and sister chromatid cohesion is prematurely lost during the meiotic divisions. We conclude that HTP-1 is central to the mechanism linking crossovers with late-prophase bivalent differentiation and defines the domains where cohesion will be protected until meiosis II. Further, we discuss parallels between the pattern of HTP-1/2 removal in response to crossovers and the phenomenon of crossover interference.[Keywords: Meiosis; chromosome axes; crossover; sister chromatid cohesion; chromosome remodeling; crossover interference] Supplemental material is available at http://www.genesdev.org. Received May 12, 2008; revised version accepted August 18, 2008. In sexually reproducing organisms, diploid germ cells produce haploid gametes through the specialized cell division program of meiosis. At the onset of meiosis, DNA is replicated and sister chromatid cohesion (SCC) is established (Nasmyth and Schleiffer 2004). In contrast to mitotic cell cycles, this single round of meiotic DNA replication is followed by two rounds of cell division, the first segregating homologous chromosomes (homologs), and the second segregating sister chromatids (Petronczki et al. 2003). This pattern of segregation requires an extended prophase during which chromosomes must assemble meiosis-specific axial structures, locate, and align with their homologs, stabilize this alignment through assembly of the synaptonemal complex (SC), and undergo crossover recombination events between their DNA molecules (Page and Hawley 2003). Crossovers that form in this context play a crucial role in promoting meiotic chromosome segregation, as they collaborate with SCC (on domains flanking the crossover site) to form the basis of chiasmata, cytologically visible connections between the homologs that are revealed upon SC disassembly and structural remodeling of chromosomes during late prophase (Jones 1987). Chiasmata allow homologs to remain connected while orienting away from each other toward opposite poles of the metaphase I spindle. Subsequently, the SCC that maintains the co...
In Caenorhabditis elegans, the Gli-family transcription factor TRA-1 is the terminal effector of the sex-determination pathway. TRA-1 activity inhibits male development and allows female fates. Genetic studies have indicated that TRA-1 is negatively regulated by the fem-1, fem-2, and fem-3 genes. However, the mechanism of this regulation has not been understood. Here, we present data that TRA-1 is regulated by degradation mediated by a CUL-2-based ubiquitin ligase complex that contains FEM-1 as the substrate-recognition subunit, and FEM-2 and FEM-3 as cofactors. CUL-2 physically associates with both FEM-1 and TRA-1 in vivo, and cul-2 mutant males share feminization phenotypes with fem mutants. CUL-2 and the FEM proteins negatively regulate TRA-1 protein levels in C. elegans. When expressed in human cells, the FEM proteins interact with human CUL2 and induce the proteasome-dependent degradation of TRA-1. This work demonstrates that the terminal step in C. elegans sex determination is controlled by ubiquitin-mediated proteolysis.
Short interfering RNAs (siRNAs) are a class of regulatory effectors that enforce gene silencing through formation of RNA duplexes. Although progress has been made in identifying the capabilities of siRNAs in silencing foreign RNA and transposable elements, siRNA functions in endogenous gene regulation have remained mysterious. In certain organisms, siRNA biosynthesis involves novel enzymes that act as RNAdirected RNA polymerases (RdRPs). Here we analyze the function of a Caenorhabditis elegans RdRP, RRF-3, during spermatogenesis. We found that loss of RRF-3 function resulted in pleiotropic defects in sperm development and that sperm defects led to embryonic lethality. Notably, sperm nuclei in mutants of either rrf-3 or another component of the siRNA pathway, eri-1, were frequently surrounded by ectopic microtubule structures, with spindle abnormalities in a subset of the resulting embryos. Through highthroughput small RNA sequencing, we identified a population of cellular mRNAs from spermatogenic cells that appear to serve as templates for antisense siRNA synthesis. This set of genes includes the majority of genes known to have enriched expression during spermatogenesis, as well as many genes not previously known to be expressed during spermatogenesis. In a subset of these genes, we found that RRF-3 was required for effective siRNA accumulation. These and other data suggest a working model in which a major role of the RRF-3/ERI pathway is to generate siRNAs that set patterns of gene expression through feedback repression of a set of critical targets during spermatogenesis.
Organisms that reproduce sexually must reduce their chromosome number by half during meiosis to generate haploid gametes. To achieve this reduction in ploidy, organisms must devise strategies to couple sister chromatids so that they stay together during the first meiotic division (when homologous chromosomes separate) and then segregate away from one another during the second division. Here we review recent findings that shed light on how Caenorhabditis elegans, an organism with holocentric chromosomes, deals with these challenges of meiosis by differentiating distinct chromosomal subdomains and remodeling chromosome structure during prophase. Furthermore, we discuss how features of chromosome organization established during prophase affect later chromosome behavior during the meiotic divisions. Finally, we illustrate how analysis of holocentric meiosis can inform our thinking about mechanisms that operate on monocentric chromosomes.During sexual reproduction, diploid chromosome number must be reduced in half to generate haploid gametes. This reduction in chromosome number is accomplished during meiosis, a specialized cell division program in which a single round of DNA replication is followed by two rounds of chromosome segregation. During prophase of meiosis I, homologous chromosomes pair, align, and undergo crossover recombination between their DNA molecules. These crossovers collaborate with sister chromatid cohesion (SCC) to create temporary physical links, called chiasmata, that connect homologs and allow them to orient and then segregate toward opposite poles of the meiosis I spindle, thereby achieving reduction in ploidy. The reductional meiosis I division is followed by an equational meiosis II division, akin to mitosis, in which sister chromatids are segregated to opposite spindle poles.Chromosome segregation during meiosis presents two special challenges for the cell division machinery: (1) SCC must be released in two steps. This is necessary to allow release of chiasmata and reductional segregation in meiosis I, while retaining a local region of sister cohesion necessary to align chromosomes and to maintain sister connections until anaphase of meiosis II. (2) Sister chromatids must be temporarily ''co-oriented'' during meiosis I, so that they move together to the same spindle pole. Sister chromatids must then switch their behavior, becoming ''bioriented'' on the meiosis II spindle so that they can move apart toward opposite spindle poles.In organisms with monocentric chromosomes, the single localized centromere serves as the focal point for mechanisms that serve to co-orient sister chromatids at meiosis I and for mechanisms that promote local protection of cohesion to allow two-step release of SCC (Sakuno and Watanabe 2009). In contrast, organisms with holocentric chromosomes, which do not have a localized centromere, cannot rely on a single predefined site to regulate sister chromatid co-orientation and the two-step loss of cohesion during meiosis.Although monocentric chromosome organization is more...
TRA-1A is the sole representative in Caenorhabditis elegans of the Gli transcription factor family. Its activity is required to specify all somatic female cell fates in XX hermaphrodites. We have found that TRA-1 protein levels are much higher in hermaphrodites than in males, and that the difference is attributable to the predominance in hermaphrodites of C-terminally truncated isoforms that are nearly undetectable in males. Our results support a model in which TRA-1A is negatively regulated by male-specific proteolysis that depends upon specific TRA-1A protein sequences and upon the activity of the fem genes. C-terminally truncated TRA-1 isoforms are stable and can inappropriately feminize XO males, suggesting that they escape this negative regulation. Thus, although C. elegans appears to lack a Hedgehog-signaling pathway, our results indicate that proteolytic processing and degradation of Gli family transcription factors, commonly seen during Hedgehog signaling in other organisms, also control C. elegans sex determination.
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