The let-7 MicroRNA Family Members mir-48, mir-84, and mir-241 Function Together to Regulate Developmental Timing in Caenorhabditis elegans

Abbott, Allison L.; Alvarez-Saavedra, Ezequiel; Miska, Eric A.; Lau, Nelson C.; Bartel, David P.; Horvitz, H. Robert; Ambros, Victor R.

doi:10.1016/j.devcel.2006.01.010

Cited by 89 publications

(155 citation statements)

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“…and hbl-1, which is targeted by mir-48, mir-84, mir-241, let-7 and lin-4(Abrahante et al, 2003;Lin et al, 2003;Abbott et al, 2005). As predicted, AIN-1 and AIN-2 mediate translational repression and degradation of miRNA target mRNAs.…”

supporting

confidence: 67%

“…Moreover, in wild-type animals, polysome association of daf-12 and lin-41 is decreased at L4 compared with L3 stage, consistent with the establishment of an inhibitory mechanism affecting translation initiation as let-7 expression starts. A more moderate decrease of polysome association is also seen when performing this comparison for let-7 mutant animals, suggesting that the n2853 allele may provide residual let-7 activity or that alternative mechanisms, possibly the let-7 sister miRNAs mir-48, mir-84 and mir-241 (Abbott et al, 2005;Li et al, 2005), may contribute.…”

Section: Translational Blockade Of Endogenous Let-7 Target Genesmentioning

confidence: 85%

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Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins

Ding

Großhans

2009

EMBO J

121

115

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MicroRNAs (miRNAs) repress target genes through a poorly defined antisense mechanism. Cell-free and cell-based assays have supported the idea that miRNAs repress their target mRNAs by blocking initiation of translation, whereas studies in animal models argued against this possibility. We examined endogenous targets of the let-7 miRNA, an important regulator of stem cell fates. We report that let-7 represses translation initiation in Caenorhabditis elegans, demonstrating this mode of action for the first time in an organism. Unexpectedly, although the lin-4 miRNA was previously reported to repress its targets at a step downstream of translation initiation, we also observe repression of translation initiation for this miRNA. This repressive mechanism, which frequently but not always coincides with transcript degradation, requires the GW182 proteins AIN-1 and AIN-2, and acts on several mRNAs targeted by different miRNAs. Our analysis of an expanded set of endogenous miRNA targets therefore indicates widespread repression of translation initiation under physiological conditions and establishes C. elegans as a genetic system for dissection of the underlying mechanisms.

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supporting

confidence: 67%

Section: Translational Blockade Of Endogenous Let-7 Target Genesmentioning

confidence: 85%

Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins

Ding

Großhans

2009

EMBO J

121

115

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“…Next, we analyzed the genetic interaction between lin-66 and hbl-1, knowing that hbl-1 also regulates the L2/L3 transition and is regulated by the let-7-like miRNAs, mir-48, mir-84 and mir-241 (Abrahante et al, 2003;Lin et al, 2003;Abbott et al, 2005). Knocking down of hbl-1 by RNAi in lin-66 (ku423) animals resulted in an alae formation phenotype that reflected a mutual suppression of mutating the two genes, suggesting that lin-66 is unlikely to act upstream of hbl-1 (Table I).…”

Section: Lin-66 Acts Upstream Of Lin-28 To Regulate Developmental Timingmentioning

confidence: 99%

“…An alternative explanation is that alg-1 plays a more prominent role in the L2/L3 transition by regulating another factor, likely the hbl-1 gene, which encodes a hunchback-like transcription factor and was shown to regulate the L2/L3 and L4/adult transitions (Fay et al, 1999;Abrahante et al, 2003;Lin et al, 2003). Recently, it has been shown that three let-7 family miRNAs (mir-48, mir-84 and mir-241) redundantly regulate the L2-to-L3 transition mainly by repressing hbl-1 expression (Abbott et al, 2005). Therefore, the L2 reiteration phenotype of alg-1 (lf) is likely due, to a large extent, to the disruption of the regulation of hbl-1 by these miRNAs.…”

Section: Functional Relationships Of Lin-66 With Alg-1 and Hbl-1mentioning

confidence: 99%

Multiple mechanisms are involved in regulating the expression of the developmental timing regulator lin-28 in Caenorhabditis elegans

Morita

Han

2006

EMBO J

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The timing of postembryonic developmental programs in Caenorhabditis elegans is regulated by a set of so-called heterochronic genes, including lin-28 that specifies second larval programs. lin-66 mutations described herein cause delays in vulval and seam cell differentiation, indicating a role for lin-66 in timing regulation. A mutation in daf-12/ nuclear receptor or alg-1/argonaute dramatically enhances the retarded phenotypes of the lin-66 mutants, and these phenotypes are suppressed by a lin-28 null allele. We further show that the LIN-28 protein level is upregulated in the lin-66 mutants and that this regulation is mediated by the 3 0 UTR of lin-28. We have also identified a potential daf-12-response element within lin-28 3 0 UTR and show that two microRNA (miRNA) (lin-4 and let-7)-binding sites mediate redundant inhibitory activities that are likely lin-66-independent. Quantitative PCR data suggest that the lin-28 mRNA level is affected by lin-14 and miRNA regulation, but not by daf-12 and lin-66 regulation. These results suggest that lin-28 expression is regulated by multiple independent mechanisms including LIN-14-mediated upregulation of mRNA level, miRNAs-mediated RNA degradation, LIN-66-mediated translational inhibition and DAF-12-involved translation promotion.

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“…For example, there are six miRNAs that share the same 5 0 seed sequence with the let-7 miRNA: miR-48, miR-241, and miR-84, whose roles in developmental timing are described below, and the less characterized miR-793, miR-794, and miR-795 ( Fig. 1) (Abbott et al, 2005;Ruby et al, 2006). There is one miRNA, miR-237, that shares a seed sequence with the lin-4 miRNA, but its deletion alone does not cause major morphological defects (Miska et al, 2007) and a heterochronic phenotype has not been reported.…”

Section: Discovery Of Mirnas In Timing and Beyondmentioning

confidence: 99%

miRNAs give worms the time of their lives: Small RNAs and temporal control in Caenorhabditis elegans

Resnick

McCulloch

Rougvie

2010

Developmental Dynamics

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Alteration in the timing of particular developmental events can lead to major morphological changes that have profound effects on the life history of an organism. Insights into developmental timing mechanisms have been revealed in the model organism C. elegans, in which a regulatory network of heterochronic genes times events during larval development, ensuring that stage-specific programs occur in the appropriate sequence and on schedule. Developmental timing studies in C. elegans led to the landmark discovery of miRNAs and continue to enhance our understanding of the regulation and activity of these small regulatory molecules. Current views of the heterochronic gene pathway are summarized here, with a focus on the ways in which miRNAs contribute to temporal control and how miRNAs themselves are regulated. Finally, the conservation of heterochronic genes and their functions in timing, as well as their related roles in stem cells and cancer are highlighted.

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The let-7 MicroRNA Family Members mir-48, mir-84, and mir-241 Function Together to Regulate Developmental Timing in Caenorhabditis elegans

Cited by 89 publications

References 0 publications

Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins

Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins

Multiple mechanisms are involved in regulating the expression of the developmental timing regulator lin-28 in Caenorhabditis elegans

miRNAs give worms the time of their lives: Small RNAs and temporal control in Caenorhabditis elegans

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