miRNAs cooperate in apoptosis regulation during <i>C. elegans</i> development

Sherrard, Ryan; Luehr, Sebastian; Holzkamp, Heinke; McJunkin, Katherine; Memar, Nadin; Conradt, Barbara

doi:10.1101/gad.288555.116

Cited by 42 publications

(37 citation statements)

References 74 publications

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“…One major question concerns the mechanisms utilized to prevent inappropriate death of these cells. Recent work by Sherrard et al provided some important insights, where microRNAs mir-35 and mir-58 promote survival of sister cells in somatic lineages of the C. elegans embryo by targeting egl-1 transcripts [27]. However, embryonic cells in this organism do not exist in a syncytium, are fated to die during specific stages of development, and do not undergo apoptosis in response to stress.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of seven of the eight mir-35 family members (mir- [35][36][37][38][39][40][41] by the gk262 allele, where only mir-42 is expressed, causes partially penetrant embryonic lethality [24][25][26]. The mir-35 family suppresses somatic cell apoptosis during embryonic development [27], but it is not known if this mode of regulation is relevant to stress-induced apoptosis in the germline.…”

Section: Introductionmentioning

confidence: 99%

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MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways

et al. 2019

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Apoptosis is a genetically programmed cell death process with profound roles in development and disease. MicroRNAs modulate the expression of many proteins and are often deregulated in human diseases, such as cancer. C. elegans germ cells undergo apoptosis in response to genotoxic stress by the combined activities of the core apoptosis and MAPK pathways, but how their signalling thresholds are buffered is an open question. Here we show mir-35-42 miRNA family play a dual role in antagonizing both NDK-1, a positive regulator of MAPK signalling, and the BH3-only pro-apoptotic protein EGL-1 to regulate the magnitude of DNA damage-induced apoptosis in the C. elegans germline. We show that while miR-35 represses EGL-1 by promoting transcript degradation, repression of NDK-1 may be through sequestration of the transcript to inhibit translation. Importantly, dramatic increase in NDK-1 expression was observed in cells about to die. In the absence of miR-35, increased NDK-1 activity enhanced MAPK signalling that lead to significant increases in germ cell death. Our findings demonstrate that NDK-1 acts upstream of (or in parallel to) EGL-1, and that miR-35 targets both egl-1 and ndk-1 to fine-tune cell killing in response to genotoxic stress.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways

et al. 2019

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“…A recent study showed that egl-1 is already transcribed in the mother of cells destined to die, but two miRNA families, the highly expressed mir-35 and mir-58 family miRNAs, co-target egl-1 to maintain its dose below a certain threshold. Accordingly, loss of these miRNAs results in premature death of those cells in which egl-1 is de-repressed above that threshold (Sherrard et al, 2017). Interestingly, the mir-58 family shares sequence homology with Drosophila bantam, suggesting functional conservation, even though their targets are not related.…”

Section: Apoptosismentioning

confidence: 99%

“…Other cases of miRNAs acting within different genetic pathways can be inferred from a study in which several C. elegans miRNA mutants that display no defects on their own, exhibit phenotypes in different sensitized genetic backgrounds (Brenner et al, 2010). A case of two different miRNAs targeting the same mRNA has been recently reported in C. elegans: mir-35 and mir-58 family miRNAs cooperate to keep the trigger of apoptosis, EGL-1, below a certain threshold, preventing precocious cell death during embryonic development (Sherrard et al, 2017). robustness are the concepts that have been considered most extensively (e.g. Alvarez-Saavedra and Horvitz, 2010;Posadas and Carthew, 2014).…”

Section: Box 1 Functional Redundancies Among Mirnasmentioning

confidence: 99%

A framework for understanding the roles of miRNAs in animal development

2017

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MicroRNAs (miRNAs) contribute to the progressive changes in gene expression that occur during development. The combined loss of all miRNAs results in embryonic lethality in all animals analyzed, illustrating the crucial role that miRNAs play collectively. However, although the loss of some individual miRNAs also results in severe developmental defects, the roles of many other miRNAs have been challenging to uncover. This has been mostly attributed to their proposed function as tuners of gene expression or providers of robustness. Here, we present a view of miRNAs in the context of development as a hierarchical and canalized series of gene regulatory networks. In this scheme, only a fraction of embryonic miRNAs act at the top of this hierarchy, with their loss resulting in broad developmental defects, whereas most other miRNAs are expressed with high cellular specificity and play roles at the periphery of development, affecting the terminal features of specialized cells. This view could help to shed new light on our understanding of miRNA function in development, disease and evolution.

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“…The miR-35 fam and -51 fam are broadly conserved, with miR-51 being a homolog of miR-100, the most ancient animal miRNA (12,27). Yet, the functions of these two miRNA families remain poorly understood and neither has been linked to mRNA targets that explain the penetrant embryonic lethality (12,(28)(29)(30)(31)(32). Zebrafish miR-430 is expressed in the zygote, where it plays a role in maternal mRNA clearance (4).…”

mentioning

confidence: 99%

Two microRNAs are sufficient for embryogenesis in C. elegans

Dexheimer

Wang

Cochella

2020

Preprint

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The Microprocessor, composed of Drosha and Pasha/DGCR8, is necessary for the biogenesis of canonical microRNAs (miRNAs) and essential for animal embryogenesis. However, the cause for this requirement is largely unknown: the Microprocessor may be required to produce one or few essential miRNAs, or many individually non-essential miRNAs. Additionally, Drosha and Pasha/ DGCR8 may be required for processing non-miRNA substrates. To distinguish between these possibilities, we developed a system in C. elegans to stringently deplete embryos of Microprocessor activity. Microprocessor-depleted embryos fail to undergo morphogenesis or form organs. We show that this early embryonic arrest is rescued by the addition of two miRNAs from the miR-35 and miR-51 families, resulting in morphologically normal larvae. Thus, just two canonical miRNAs are sufficient for morphogenesis and organogenesis, and the processing of these miRNAs accounts for the essential requirement for Drosha and Pasha/DGCR8 during C. elegans embryonic development.

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miRNAs cooperate in apoptosis regulation during C. elegans development

Cited by 42 publications

References 74 publications

MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways

MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways

A framework for understanding the roles of miRNAs in animal development

Two microRNAs are sufficient for embryogenesis in C. elegans

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