Academic journal article Genetics

Germline Stem Cell Differentiation Entails Regional Control of Cell Fate Regulator GLD-1 in Caenorhabditis Elegans

Academic journal article Genetics

Germline Stem Cell Differentiation Entails Regional Control of Cell Fate Regulator GLD-1 in Caenorhabditis Elegans

Article excerpt

NOTCH signaling is a highly conserved pathway that contributes to stem cell maintenance and differentiation in a variety of developmental and organismal contexts (Bray 2006; Liu et al. 2010; Andersson et al. 2011). Notch signaling control of stem cell maintenance and differentiation is typified by a source cell, providing ligand to a limited number of recipient, receptor-expressing cells. The Caenorhabditis elegans germline provides a unique context for Notch-mediated control of a stem cell population, where the glp-1 Notch signaling receptor gives rise to the polarized pattern of germline stem cell differentiation. Under optimal growth conditions, germline stem cell differentiation into meiotic prophase spans an ~30-cell diameter region of .250 cells in the distal region of the adult hermaphrodite gonad (Kimble and Crittenden 2007; Byrd and Kimble 2009; Hansen and Schedl 2013) (Figure 1A). A relatively large pool of stem cells (~60-80 cells) is maintained through glp-1 signaling activation triggered by ligands expressed by a large and complex somatic gonad cell called the distal tip cell (DTC) (Kimble and White 1981; Austin and Kimble 1987; Henderson et al. 1994; Tax et al. 1994; Nadarajan et al. 2009; Byrd et al. 2014; Fox and Schedl 2015). As germ cells are displaced out of reach of the DTC, glp-1 signaling is thought to drop below a threshold level of activity; then, after completing their ongoing mitotic cell cycle (terminal mitosis), daughters enter meiotic S and subsequently overtly adopt the meiotic fate by beginning leptotene/zygotene (Figure 1A). This polarized stem cell differentiation pattern is ideal for rapid generation of large numbers of meiotic prophase cells under optimal conditions for progeny production (Fox and Schedl 2015).

The mechanism whereby glp-1 mediates control over a large population of germline stem cells is not well understood. Previous genetic analysis by others and us demonstrated that glp-1 maintains the germline stem cell fate through repression of at least three redundant genetic pathways called the gld-1, gld-2, and third meiotic entry pathways (Kadyk and Kimble 1998; Eckmann et al. 2004; Hansen et al. 2004a; Fox et al. 2011). The gld-1 pathway includes the gld-1 and nos-3 genes. gld-1 encodes an RNA binding protein that inhibits germline stem cell fate and/or promotes meiotic entry through translational repression of mitotic genes (Biedermann et al. 2009; Fox et al. 2011; Jungkamp et al. 2011). nos-3 encodes an RNA binding protein related to Drosophila Nanos (Kraemer et al. 1999), a known translational repressor. nos-3 promotes meiotic entry at least in part through controlling GLD-1 levels and/or activity (Hansen et al. 2004b), but how it mediates this activity is unknown. The gld-2 pathway includes gld-2 and gld-3 (Kadyk and Kimble 1998; Eckmann et al. 2004; Hansen et al. 2004a; Schmid et al. 2009). gld-2 encodes a cytoplasmic poly-A polymerase that promotes translation of meiotic entry genes to inhibit germline stem cell fate and/or promote meiotic entry (Wang et al. 2002; Suh et al. 2006; Kim et al. 2010). gld-3 encodes an RNA binding protein that promotes meiotic entry by facilitating gld-2 interaction with its direct targets (Suh et al. 2006; Schmid et al. 2009). Genetic analysis of mutants lacking both gld-1 and gld-2 pathway genes revealed the existence of at least a thirdmeiotic entry pathway (Hansen et al. 2004a; Fox et al. 2011), but the identity of genes that act in this pathway are currently unknown. Meiotic entry occurs normally in mutants lacking genes representing any one pathway (i.e., gld-1 or gld-2 single mutants), but meiotic entry is impaired in mutants lacking genes from separate pathways (i.e., gld-1 gld-2 double mutants), highlighting that these genes are not individually required for meiotic entry.

The activity and or levels of the gld-1 and gld-2 pathway genes are responsive to glp-1 signaling activity. For example, GLD-1 levels are high in distal germ cells in the absence of glp-1, and GLD-1 levels remain low when glp-1 signaling is ectopically high (Hansen et al. …

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