Translational control in the C. elegans hermaphrodite germ line

Genome ◽  
2010 ◽  
Vol 53 (2) ◽  
pp. 83-102 ◽  
Author(s):  
Hilary Racher ◽  
Dave Hansen

The formation of a fully developed gamete from an undifferentiated germ cell requires progression through numerous developmental stages and cell fate decisions. The precise timing and level of gene expression guides cells through these stages. Translational regulation is highly utilized in the germ line of many species, including Caenorhabditis elegans , to regulate gene expression and ensure the proper formation of gametes. In this review, we discuss some of the developmental stages and cell fate decisions involved in the formation of functional gametes in the C. elegans germ line in which translational control has been implicated. These stages include the mitosis versus meiosis decision, the sperm/oocyte decision, and gamete maturation. We also discuss some of the techniques used to identify mRNA targets; the identification of these targets is necessary to clearly understand the role each RNA-binding protein plays in these decisions. Relatively few mRNA targets have been identified, thus providing a major focus for future research. Finally, we propose some reasons why translational control may be utilized so heavily in the germ line. Given that many species have this substantial reliance on translational regulation for the control of gene expression in the germ line, an understanding of translational regulation in the C. elegans germ line is likely to increase our understanding of gamete formation in general.

2015 ◽  
Vol 5 (3) ◽  
pp. 353-359 ◽  
Author(s):  
Yunting Chen ◽  
Iva Greenwald

Abstract Notch is a receptor that mediates cell–cell interactions that specify binary cell fate decisions in development and tissue homeostasis. Inappropriate Notch signaling is associated with cancer, and mutations in Notch pathway components have been associated with developmental diseases and syndromes. In Caenorhabditis elegans, suppressors of phenotypes associated with constitutively active LIN-12/Notch have identified many conserved core components and direct or indirect modulators. Here, we molecularly identify sel(ar584), originally isolated as a suppressor of a constitutively active allele of lin-12. We show that sel(ar584) is an allele of hecd-1, the ortholog of human HECDT1, a ubiquitin ligase that has been implicated in several different mammalian developmental events. We studied interactions of hecd-1 with lin-12 in the somatic gonad and with the other C. elegans Notch gene, glp-1, in the germ line. We found that hecd-1 acts as a positive modulator of lin-12/Notch activity in a somatic gonad context—the original basis for its isolation—but acts autonomously as a negative modulator of glp-1/Notch activity in the germ line. As the yeast ortholog of HECD-1, Ufd4p, has been shown to function in quality control, and C. elegans  HECD-1 has been shown to affect mitochondrial maintenance, we propose that the different genetic interactions between hecd-1 and Notch genes we observed in different cell contexts may reflect differences in quality control regulatory mechanisms or in cellular metabolism.


eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sachin Sethi ◽  
Jing W Wang

Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages. We further show that this system can be used to control in vivo gene expression levels with low background, large dynamic range, and in a reversible manner without detectable side effects on the lifespan or behavior of the animal. Additionally, we engineered tools for chemically controlling gene expression (GAL80-DD) and recombination (FLP-DD). We demonstrate the applicability of this technology in manipulating neuronal activity and for high-efficiency sparse labeling of neuronal populations.


2017 ◽  
Author(s):  
Sachin Sethi ◽  
Jing W. Wang

AbstractSeveral techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages. We further show that this system can be used to control in vivo gene expression levels with low background, large dynamic range, and in a reversible manner without detectable side effects on the lifespan or behavior of the animal. Additionally, we engineered tools for chemically controlling gene expression (GAL80-DD) and recombination (FLP-DD). We demonstrate the applicability of this technology in manipulating neuronal activity and for high-efficiency sparse labeling of neuronal populations.


2022 ◽  
Author(s):  
Kimberly N. Bekas ◽  
Bryan T. Phillips

Asymmetric cell division (ACD) is a fundamental mechanism of developmental cell fate specification and adult tissue homeostasis. In C. elegans, the Wnt/beta-catenin asymmetry (WβA) pathway regulates ACDs throughout embryonic and larval development. Under control of Wnt ligand-induced polarity, the transcription factor TCF/POP-1 functions with the coactivator beta-catenin/SYS-1 to activate gene expression in the signaled cell or, in absence of the coactivator, to repress Wnt target genes in the nascent unsignaled daughter cell. To date, a broad investigation of Groucho function in WβA is lacking and the function of the short Groucho AES homolog, lsy-22 has only been evaluated in C. elegans neuronal cell fate decisions. Further, there is conflicting evidence showing TCF utilizing Groucho-mediated repression may be either aided or repressed by addition of AES subfamily of Groucho proteins. Here we demonstrate a genetic interaction between Groucho repressors and TCF/POP-1 in ACDs in the somatic gonad, the seam hypodermal stem cell lineage and the early embryo. Specifically, in the somatic gonad lineage, the signaled cell fate increases after individual and double Groucho loss of function, representing the first demonstration of Groucho function in wild-type WβA ACD. Further, WβA target gene misexpression occurs at a higher rate than DTC fate changes, suggesting derepression generates an intermediate cell fate. In seam cell ACD, loss of Groucho unc-37 or Groucho-like lsy-22 in a pop-1(RNAi) hypomorphic background enhances a pop-1 seam cell expansion and target gene misregulation. Moreover, while POP-1 depletion in lsy-22 null mutants yielded an expected increase in seam cells we observed a surprising seam cell decrease in the unc-37 null subjected to POP-1 depletion. This phenotype may be due to UNC-37 regulation of pop-1 expression in this tissue since we find misregulation of POP-1 in unc-37 mutants. Lastly, Groucho functions in embryonic endoderm development since we observe ectopic endoderm target gene expression in lsy-22(ot244) heterozygotes and unc-37(tm4649) heterozygotes subjected to intermediate levels of hda-1(RNAi). Together, these data indicate Groucho repressor modulation of cell fate via regulation of POP-1/TCF repression is widespread in asymmetric cell fate decisions and suggests a novel role of LSY-22 as a bona fide TCF repressor. As AES Grouchos are well-conserved, our model of combinatorial TCF repression by both Gro/TLE and AES warrants further investigation. 


2018 ◽  
Vol 217 (7) ◽  
pp. 2247-2259 ◽  
Author(s):  
Juan Manuel Schvartzman ◽  
Craig B. Thompson ◽  
Lydia W.S. Finley

Dynamic regulation of gene expression in response to changing local conditions is critical for the survival of all organisms. In metazoans, coherent regulation of gene expression programs underlies the development of functionally distinct cell lineages. The cooperation between transcription factors and the chromatin landscape enables precise control of gene expression in response to cell-intrinsic and cell-extrinsic signals. Many of the chemical modifications that decorate DNA and histones are adducts derived from intermediates of cellular metabolic pathways. In addition, several of the enzymes that can remove these marks use metabolites as part of their enzymatic reaction. These observations have led to the hypothesis that fluctuations in metabolite levels influence the deposition and removal of chromatin modifications. In this review, we consider the emerging evidence that cellular metabolic activity contributes to gene expression and cell fate decisions through metabolite-dependent effects on chromatin organization.


Science ◽  
2011 ◽  
Vol 333 (6047) ◽  
pp. 1311-1314 ◽  
Author(s):  
Cheryl L. Johnson ◽  
Andrew M. Spence

RNA can act as a regulator of gene expression with roles in transposon silencing, antiviral defense, and cell fate determination. Here, we show that in Caenorhabditis elegans a maternal transcript of the sex-determining gene fem-1 is required to license expression of a wild-type fem-1 allele in the zygotic germ line. Females homozygous for fem-1 deletions produce heterozygous offspring exhibiting germline feminization, reduced fem-1 activity, and transcript accumulation. Injection of fem-1 RNA incapable of encoding a protein into the maternal germ line rescues this defect in the progeny. The defect in zygotic fem-1 expression is heritable, suggesting that the gene is subject to epigenetic silencing that is prevented by maternal fem-1 transcripts. This mechanism may contribute to protecting the identity and integrity of the germ line.


2018 ◽  
Author(s):  
Brian S. Clark ◽  
Genevieve L. Stein-O’Brien ◽  
Fion Shiau ◽  
Gabrielle H. Cannon ◽  
Emily Davis ◽  
...  

SUMMARYPrecise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the extensive cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single cell RNA-sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each of the major retinal cell types. These data identify transitions in gene expression between early and late-stage retinal progenitors, as well as a classification of neurogenic progenitors. We identify here the NFI family of transcription factors (Nfia, Nfib, and Nfix) as genes with enriched expression within late RPCs, and show they are regulators of bipolar interneuron and Müller glia specification and the control of proliferative quiescence.


2017 ◽  
Author(s):  
Celia María Muñoz-Jiménez ◽  
Cristina Ayuso ◽  
Agnieszka Dobrzynska ◽  
Antonio Torres ◽  
Patricia de la Cruz Ruiz ◽  
...  

AbstractSite-specific recombinases are potent tools to regulate gene expression. In particular, the Cre and FLP enzymes are widely used to either activate or inactivate genes in a precise spatiotemporal manner. Both recombinases work efficiently in the popular model organism Caenorhabditis elegans but their use in this nematode is still only sporadic. To increase the utility of the FLP system in C. elegans we have generated a series of single-copy transgenic strains that stably express an optimized version of FLP in specific tissues or by heat induction. We show that recombination efficiencies reach 100 percent in several cell types, such as muscles, intestine and serotonin producing neurons. Moreover, we demonstrate that most promoters drive recombination exclusively in the expected tissues. As examples of the potentials of the FLP lines we describe novel tools for induced cell ablation by expression of the PEEL-1 toxin and a versatile FLP-out cassette for generation of GFP-tagged conditional knockout alleles. Together with other recombinase-based reagents created by the C. elegans community this toolkit increases the possibilities for detailed analyses of specific biological processes at developmental stages inside intact animals.


2020 ◽  
Author(s):  
Thomas G Minchington ◽  
Sam Griffiths-Jones ◽  
Nancy Papalopulu

AbstractConcepts from dynamical systems theory, including multi-stability, oscillations, robustness and stochasticity, are increasingly implicated in the control of gene expression during cell fate decisions, inflammation and stem cell heterogeneity. However, the prevalence of the underlying structures within gene networks which drive these dynamical behaviours, such as direct autoregulation or feedback by microRNAs, is unknown.We integrate transcription factor binding site (TFBS) and microRNA target data to generate a gene interaction network across 28 human tissues. This network was interrogated to identify network motifs capable of driving dynamical gene expression, in particular oscillations. Autoregulatory motifs were identified in 56% of transcription factors (TFs) investigated, 89% of which were also found in dual feedback motifs with a microRNA. Both the autoregulatory and dual feedback motifs were enriched in the network. TFs that autoregulate were found to be highly conserved between tissues. Dual feedback motifs with microRNAs were also conserved, but less so. Such dual feedback motifs were conserved between tissues, although TFs regulate different combinations of microRNAs in a tissue-dependent manner.TFs which autoregulate are prevalent among human TFs and have more interactions with microRNAs than non-autoregulatory genes. The enrichment of such motifs within the human transcriptional network indicates that more genes may have interesting expression dynamics than previously thought. These data provide a resource for the identification of TFs which regulate the dynamical properties of human gene expression. These findings support the development of dynamical conceptual frameworks for the study of fundamental biological processes.


2019 ◽  
Vol 11 (10) ◽  
pp. 930-939 ◽  
Author(s):  
Michaela Müller-McNicoll ◽  
Oliver Rossbach ◽  
Jingyi Hui ◽  
Jan Medenbach

Abstract RNA-binding proteins (RBPs) are key regulators in post-transcriptional control of gene expression. Mutations that alter their activity or abundance have been implicated in numerous diseases such as neurodegenerative disorders and various types of cancer. This highlights the importance of RBP proteostasis and the necessity to tightly control the expression levels and activities of RBPs. In many cases, RBPs engage in an auto-regulatory feedback by directly binding to and influencing the fate of their own mRNAs, exerting control over their own expression. For this feedback control, RBPs employ a variety of mechanisms operating at all levels of post-transcriptional regulation of gene expression. Here we review RBP-mediated autogenous feedback regulation that either serves to maintain protein abundance within a physiological range (by negative feedback) or generates binary, genetic on/off switches important for e.g. cell fate decisions (by positive feedback).


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