Academic journal article Genetics

Coordination of Recombination with Meiotic Progression in the Caenorhabditis Elegans Germline by KIN-18, a TAO Kinase That Regulates the Timing of MPK-1 Signaling

Academic journal article Genetics

Coordination of Recombination with Meiotic Progression in the Caenorhabditis Elegans Germline by KIN-18, a TAO Kinase That Regulates the Timing of MPK-1 Signaling

Article excerpt

THE germline contains a multitude of cells that proliferate to form a population that will undergo two meiotic divisions, giving rise to gametes. In meiosis, one round of DNA replication is followed by two cell divisions reducing the ploidy of the germ cell by half. A large fraction of the cells encompassing the germline are found in meiotic prophase I. Many of the key evolutionarily conserved events that take place in this specialized prophase are aimed at preparing chromosomes for their segregation in meiosis I. One such essential and conserved event is the formation of crossovers between homologous chromosomes. During the initial stages of meiotic prophase I (leptotene/zygotene), a protein structure named the synaptonemal complex (SC) starts to assemble between homologs (MacQueen et al. 2002; Schild-Prufert et al. 2011). Concurrently, meiotic DNA double-strand breaks (DSBs) are introduced to initiate meiotic recombination (Keeney et al. 1997; Dernburg et al. 1998). As meiosis progresses, germ cells enter pachytene where the SC is fully formed and meiotic DSBs are processed and repaired. In the presence of a fully formed SC, meiotic DSBs are repaired, giving rise to crossovers by late pachytene. In most multicellular organisms, apoptosis is activated in late pachytene and reduces the number of germ cells in the developing germline (Gumienny et al. 1999). Apoptosis serves as a quality control mechanism and assists in the growth of the surviving oocytes; dying cells serve as "nurse cells" (Andux and Ellis 2008). The timely occurrence of each stage of meiosis is required for the formation of functional euploid gametes. Therefore, mechanisms assuring the timely progression of meiotic events must exist in Caenorhabditis elegans as well as in other organisms.

Mitogen-activated protein kinase (MAPK) pathways regulate intracellular signaling in response to various extracellular stimuli (Widmann et al. 1999; Pearson et al. 2001). MAPK signaling cascades consist of terminal kinase MAPK and two upstream kinases,MAP2K andMAP3K. Threewell-characterized subfamilies of MAPK are activated by specific upstream kinases in response to different stimuli: ERK, JNK, and p38 (Widmann et al. 1999; Pearson et al. 2001). The conserved ERK/MAPK-signaling cascade regulates meiotic progression in both vertebrate and invertebrate systems (Church et al. 1995; Fan and Sun 2004; Lee et al. 2007). In the C. elegans germline, the ERK ortholog MPK-1 is activated by upstream members LET-60/Ras, LIN-45/Raf (MAP3K), and MEK-2/ Mek (MAP2K) along with the scaffold protein KSR-2 (Church et al. 1995; Hsu et al. 2002; Ohmachi et al. 2002). MPK-1 activation is temporally regulated: it is activated in pachytene, deactivated in diplotene, and then reactivated in proximal diakinesis oocytes (Lee et al. 2007). MPK-1 activation at pachytene is influenced by nutrient state and is mediated by the DAF-2 pathway (Lopez et al. 2013). Loss-of-function (lf) alleles of MPK-1 pathway members arrest prior to diplotene, indicating that MPK-1 activation is essential for normal meiotic progression (Church et al. 1995; Gumienny et al. 1999). The arrested nuclei cluster and eventually degenerate (Church et al. 1995; Hsu et al. 2002; Ohmachi et al. 2002). As wild-type nuclei progress through diplotene, MPK-1 is deactivated by LIP-1, a MAPK phosphatase, and oocytes remain arrested in prophase I at diakinesis (Hajnal and Berset 2002; Rutkowski et al. 2011). Then a signal from sperm, mediated by themajor sperm protein, triggers the activation of MPK-1 in the proximal diakinesis oocyte. This activation leads to exit from meiotic prophase I and to the initiation of ovulation and the meiotic divisions (Miller et al. 2001; Kosinski et al. 2005).

Thousand And One (TAO) kinases were originally identified as mammalian homologs of Ste20 protein kinase in Saccharomyces cerevisiae (Hutchison et al. 1998; Chen et al. 1999). In mammalian tissue culture, TAO kinases function as a MAP3K that can activate p38 (MAPK) during stress response to trigger a cell cycle checkpoint (Hutchison et al. …

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