The<i>C. elegans</i>heterochronic gene<i>lin-46</i>affects developmental timing at two larval stages and encodes a relative of the scaffolding protein gephyrin

Pepper, Anita S.-R.; McCane, Jill E.; Kemper, Kevin; Yeung, Denise Au; Lee, Rosalind C.; Ambros, Victor R.; Moss, Eric G.

doi:10.1242/dev.01098

Cited by 44 publications

(79 citation statements)

References 34 publications

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“…To further investigate mir-237's relationship to lin-46, we utilized lin-28(n719); lin-46(ma164) double mutant animals. Mutations in both lin-28 and lin-46 cause mutual suppression of their respective heterochronic defects, making lin-28(n719); lin-46(ma164) double mutants nearly WT (compare Table 1, line 1, to Table 4, line 8) (Pepper et al 2004). In this background, loss of mir-237 caused no change in seam cell number at the L4 or in alae formation (Table 4, line 9).…”

Section: Resultsmentioning

confidence: 94%

“…lin-46 encodes a putative protein-protein interaction factor whose role in the heterochronic pathway is still poorly understood; previous work in our lab showed that lin-46 acts at the same step as lin-28, but in a nonlinear fashion, to promote L3 cell fates (Pepper et al 2004). Accordingly, lin-46(ma164) mutants reiterate the L2, causing an increased seam cell number, and form gapped alae at the end of the L4 (Table 4, line 6) (Pepper et al 2004). We found that loss of mir-237 enhances the lin-46 extra seam cell phenotype (Table 4, compare lines 6 and 7).…”

Section: Resultsmentioning

confidence: 99%

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Stage-Specific Timing of the microRNA Regulation oflin-28by the Heterochronic Genelin-14inCaenorhabditis elegans

et al. 2017

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In normal development, the order and synchrony of diverse developmental events must be explicitly controlled. In the nematode Caenorhabditis elegans, the timing of larval events is regulated by hierarchy of proteins and microRNAs (miRNAs) known as the heterochronic pathway. These regulators are organized in feedforward and feedback interactions to form a robust mechanism for specifying the timing and execution of cell fates at successive stages. One member of this pathway is the RNA binding protein LIN-28, which promotes pluripotency and cell fate decisions in successive stages. Two genetic circuits control LIN-28 abundance: it is negatively regulated by the miRNA lin-4, and positively regulated by the transcription factor LIN-14 through a mechanism that was previously unknown. In this report, we used animals that lack lin-4 to elucidate LIN-14's activity in this circuit. We demonstrate that three let-7 family miRNAs-miR-48, miR-84, and miR-241-inhibit lin-28 expression. Furthermore, we show genetically that these miRNAs act between lin-14 and lin-28, and that they comprise the pathway by which lin-14 positively regulates lin-28. We also show that the lin-4 family member mir-237, also regulates early cell fates. Finally, we show that the expression of these miRNAs is directly inhibited by lin-14 activity, making them the first known targets of lin-14 that act in the heterochronic pathway.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Stage-Specific Timing of the microRNA Regulation oflin-28by the Heterochronic Genelin-14inCaenorhabditis elegans

et al. 2017

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“…The expression of lin-28 is limited to the early phase of development, rapidly decreasing after the second larval molt, partially as a result of the regulatory action of the miRNA lin-4 (Moss et al 1997). lin-28 interacts genetically with other heterochronic genes: The persistent expression of lin-14 requires LIN-28, while the lin-28 mutant phenotype can be suppressed by mutations in lin-46 (Arasu et al 1991;Pepper et al 2004). Furthermore, mutation of let-7 partially rescues the precocious differentiation of seam cells in lin-28 mutants, and lin-28 is required for the correct temporal expression of let-7 (Reinhart et al 2000;Johnson et al 2003;Van Wynsberghe et al 2011).…”

Section: Introductionmentioning

confidence: 99%

A novel mechanism of LIN-28 regulation oflet-7microRNA expression revealed by in vivo HITS-CLIP inC. elegans

Stefani

Chen

Zhao

et al. 2015

RNA

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The evolutionarily conserved gene lin-28 encodes an RNA-binding protein and is an important regulator of the proper temporal succession of several developmental events in both invertebrates and vertebrates. At the cellular level, LIN-28 promotes stemness and proliferation, and inhibits differentiation, a feature best illustrated by its ability to induce pluripotency when ectopically expressed in human fibroblasts in combination with NANOG, OCT4, and SOX2. Mammalian LIN28 functions in part by regulating processing of the let-7 microRNA through a GGAG binding site in the pre-let-7's distal loop region. However, many human and animal let-7 precursors lack the GGAG binding motif. In order to dissect the molecular mechanisms underlying its biological functions in a living animal, we identified a map of LIN-28 interactions with the transcriptome by in vivo HITS-CLIP in Caenorhabditis elegans. LIN-28 binds a large pool of messenger RNAs, and a substantial fraction of the bona fide LIN-28 targets are involved in aspects of animal development. Furthermore, our data show that LIN-28 regulates the expression of the let-7 microRNA by binding its primary transcript in a previously unknown region, revealing a novel regulatory mechanism.

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“…The retarded heterochronic defects and the reiteration of the S2 division in lin-46 mutants are also partially suppressed by a sop-2 mutation (Pepper et al 2004). Fiftyfive percent of sop-2; lin-46 mutants (n ¼ 22) displayed full fusion of seam cells at the late L4 stage, compared to 18% in lin-46 single mutants (n ¼ 22).…”

Section: Resultsmentioning

confidence: 98%

The Caenorhabditis elegans PcG-like Gene sop-2 Regulates the Temporal and Sexual Specificities of Cell Fates

et al. 2008

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How spatial, temporal, and sexual specific cues are integrated to specify distinct cell fates during multicellular organism development is largely unknown. Here we demonstrate that the Caenorhabditis elegans PcG-like gene sop-2 determines the temporal and sexual specificities of a row of hypodermal seam cells, in addition to specifying their positional identities. Loss-of-function of sop-2 causes premature expression of adult fates at larval stages. sop-2 acts upstream of lin-29 in the heterochronic pathway and genetically interacts with other heterochronic genes in specifying the temporal fates of seam cells at different larval stages. We show that the number of ALG-1-containing P bodies is increased in seam cells in sop-2 mutants. Furthermore, the microRNA-mediated repression of a heterochronic gene reporter is enhanced in sop-2 mutants. Mutations in sop-2 also cause partial hermaphrodite-to-male sexual transformations. The homeotic transformations, heterochronic defects, and sexual transformations can occur concomitantly in sop-2 mutants. In summary, our studies reveal that sop-2 integrates spatial, temporal, and sexual cues during C. elegans development.

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TheC. elegansheterochronic genelin-46affects developmental timing at two larval stages and encodes a relative of the scaffolding protein gephyrin

Cited by 44 publications

References 34 publications

Stage-Specific Timing of the microRNA Regulation oflin-28by the Heterochronic Genelin-14inCaenorhabditis elegans

Stage-Specific Timing of the microRNA Regulation oflin-28by the Heterochronic Genelin-14inCaenorhabditis elegans

A novel mechanism of LIN-28 regulation oflet-7microRNA expression revealed by in vivo HITS-CLIP inC. elegans

The Caenorhabditis elegans PcG-like Gene sop-2 Regulates the Temporal and Sexual Specificities of Cell Fates

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