@article{548e2b29d69f490fb23fd61e289e0270,
title = "TRIM-NHL protein, NHL-2, modulates cell fate choices in the C. elegans germ line",
abstract = "Many tissues contain multipotent stem cells that are critical for maintaining tissue function. In Caenorhabditis elegans, germline stem cells allow gamete production to continue in adulthood. In the gonad, GLP-1/Notch signaling from the distal tip cell niche to neighboring germ cells activates a complex regulatory network to maintain a stem cell population. GLP-1/Notch signaling positively regulates production of LST-1 and SYGL-1 proteins that, in turn, interact with a set of PUF/FBF proteins to positively regulate the stem cell fate. We previously described sog (suppressor of glp-1 loss of function) and teg (tumorous enhancer of glp-1 gain of function) genes that limit the stem cell fate and/or promote the meiotic fate. Here, we show that sog-10 is allelic to nhl-2. NHL-2 is a member of the conserved TRIM-NHL protein family whose members can bind RNA and ubiquitinate protein substrates. We show that NHL-2 acts, at least in part, by inhibiting the expression of PUF-3 and PUF-11 translational repressor proteins that promote the stem cell fate. Two other negative regulators of stem cell fate, CGH-1 (conserved germline helicase) and ALG-5 (Argonaute protein), may work with NHL-2 to modulate the stem cell population. In addition, NHL-2 activity promotes the male germ cell fate in XX animals.",
keywords = "C. elegans, GLP-1/Notch signaling, Germline, NHL-2, Stem cell fate, TRIM-NHL proteins",
author = "Brenner, {John L.} and Jyo, {Erin M.} and Ariz Mohammad and Paul Fox and Vovanti Jones and Elaine Mardis and Tim Schedl and Maine, {Eleanor M.}",
note = "Funding Information: We identified two gene products, CGH-1 and ALG-5, that may act together with NHL-2 to influence the stem cell vs meiotic fate choice. Results supporting this possibility include that loss of each of the three genes enhances the tumorous phenotype of glp-1(ar202gf) and that loss of nhl-2 or alg-5 suppresses the premature meiotic entry phenotype of glp-1(q224) (cgh-1 was not tested). Furthermore, NHL-2 physically associates with CGH-1, as well as miRNA Argonaute proteins ALG-1 and ALG-2, in co-IPs (Hammell et al. 2009; Davis et al. 2018) (ALG-5 was not tested). Our results do not support a role for core miRNA biogenesis factors in promoting the GSC fate/inhibiting meiotic development, as assayed by enhancement of glp-1(ar202gf). In support of this negative result, in situ hybridization studies have failed to identify a germline expressed miRNA that accumulates in the progenitor zone (Minogue et al. 2018). Instead, NHL-2, ALG-5, and CGH-1 are positioned to interact with both siRNAs and PIWI-associated (pi) RNAs on P granules (Brown et al. 2017; Davis et al. 2018), and NHL-2 activity influences siRNA and piRNA abundance (Davis et al. 2018). Interestingly, the CSR-1 Argonaute complex, presumably through 22G siRNAs, promotes the GSC fate/inhibits meiotic entry (Smardon et al. 2000; She et al. 2009). Possibly, NHL-2, ALG-5, and CGH-1 function to oppose the activity of the CSR-1 complex in this decision. Alternatively, or in addition, NHL-2 and CGH-1 may modulate the GSC versus meiotic fate choice in their capacity as translational regulators independent of small RNAs. CGH-1 localizes to numerous RNP particles in the C. elegans soma and germ line where translational regulation may occur (Navarro et al. 2001; Audhya et al. 2005; Boag et al. 2005; Jud et al. 2008; Noble et al. 2008), and it stabilizes certain maternal mRNAs (Noble et al. 2008; Boag et al., 2005) and represses expression of CED-3/caspase to limit apoptosis in the oogenic germ line (Subasic et al. 2016; Navarro et al. 2001).We thank: Li Qiao and Anne Smardon for fine structure genetic mapping of q162; Maria Ow, Niko Wagner, Matt Sullenberger, and Leanne Kelley for technical advice and assistance; Judith Kimble and Zuzana Kocsisova for strains; Sarah Hall and members of the Schedl, Maine, and Hall labs for discussions; and Leanne Kelley and two anonymous reviewers for comments on the manuscript. Funding: This work was supported by the Syracuse University SOURCE program (to EMJ), the National Science Foundation (#IBN-9318709 to EMM), the National Institutes of Health (R01 GM100756 and GM63310 to TS), and BioMedRAP (to VJ). Some strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Funding Information: We thank: Li Qiao and Anne Smardon for fine structure genetic mapping of q162; Maria Ow, Niko Wagner, Matt Sullenberger, and Leanne Kelley for technical advice and assistance; Judith Kimble and Zuzana Kocsisova for strains; Sarah Hall and members of the Schedl, Maine, and Hall labs for discussions; and Leanne Kelley and two anonymous reviewers for comments on the manuscript. Funding: This work was supported by the Syracuse University SOURCE program (to EMJ), the National Science Foundation (# IBN-9318709 to EMM), the National Institutes of Health ( R01 GM100756 and GM63310 to TS), and BioMedRAP (to VJ). Some strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = nov,
doi = "10.1016/j.ydbio.2022.08.010",
language = "English",
volume = "491",
pages = "43--55",
journal = "Developmental Biology",
issn = "0012-1606",
}