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

Tsialikas, Jennifer; Romens, Mitchell A; Abbott, Allison L.; Moss, Eric G.

doi:10.1534/genetics.116.195040

Cited by 18 publications

(37 citation statements)

References 44 publications

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“…3A, B). Notably, all of these except miR-246 are known to be involved in both heterochronic development and a range of other processes [8,9,27,28], a fact that was further supported by our tissue-enrichment analysis (Additional file 5: Figure S2). We next performed quantitative real-time PCR (qRT-PCR) validations which revealed similar, if comparatively lower (3-22-fold versus 2-12-fold in RNA-Seq and qRT-PCR, respectively), DE trends (Fig.…”

Section: Heterochronic Mirna Expression Is Altered In Pry-1 Mutantssupporting

confidence: 72%

“…Together, these data allow us to conclude that miRNAs act downstream of POP-1, which agrees with a previous model [18], and also suggest that PRY-1 may interact with WRM-1, LIT-1, and POP-1 to negatively regulate the expression of heterochronic miRNAs during seam cell development. [8,39,40] as well as let-7 family members miR-48, miR-84, and miR-241 [9,17].…”

Section: Knockdowns Of Wnt Asymmetric Pathway Components Affect Both mentioning

confidence: 99%

“…Specifically, lin-4 is required for the L1-L2 transition [2,8], while the let-7 family members act at later stages of development [9]. Mutations in lin-4, miR-48, miR-84, and miR-241 cause cells to reiterate stages, which ultimately affects both the number of differentiated seam cells, and cuticle development [9].…”

Section: Introductionmentioning

confidence: 99%

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Role of PRY-1/Axin in heterochronic miRNA-mediated seam cell development

Mallick

Ranawade

Gupta

2019

Preprint

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Background Caenorhabditis elegans seam cells serve as a good model to understand how genes and signaling pathways interact to control asymmetric cell fates. The stage-specific pattern of seam cell division is coordinated by a genetic network that includes WNT asymmetry pathway components WRM-1, LIT-1, and POP-1, as well as heterochronic microRNA (miRNAs) and their downstream targets. Mutations in pry-1, a negative regulator of WNT signaling that belongs to the Axin family, were shown to cause seam cell defects; however, the mechanism of PRY-1 action and its interactions with miRNAs remain unclear. Results We found that pry-1 mutants in C. elegans exhibit seam cell, cuticle, and alae defects. To examine this further, a miRNA transcriptome analysis was carried out, which showed that let-7 (miR-48, miR-84, miR-241) and lin-4 (lin-4, miR-237) family members were upregulated in the absence of pry-1 function. Similar phenotypes and patterns of miRNA overexpression were also observed in C. briggsae pry-1 mutants, a species that is closely related to C. elegans. RNA interference-mediated silencing of wrm-1 and lit-1 in the C. elegans pry-1 mutants rescued the seam cell defect, whereas pop-1 silencing enhanced the phenotype, suggesting that all three proteins are likely important for PRY-1 function in seam cells. We also found that these miRNAs were overexpressed in pop-1 hypomorphic animals, suggesting that PRY-1 may be required for POP-1-mediated miRNA suppression. Analysis of the let-7 and lin-4-family heterochronic targets lin-28 and hbl-1 showed that both genes were significantly downregulated in pry-1 mutants, and furthermore, lin-28 silencing reduced the number of seam cells in mutant animals. Conclusions Our results show that PRY-1 plays a conserved role to maintain normal expression of heterochronic miRNAs in nematodes. Furthermore, we demonstrated that PRY-1 acts upstream of the WNT asymmetry pathway components WRM-1, LIT-1, and POP-1, and miRNA target genes in seam cell development.

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Section: Heterochronic Mirna Expression Is Altered In Pry-1 Mutantssupporting

confidence: 72%

Section: Knockdowns Of Wnt Asymmetric Pathway Components Affect Both mentioning

confidence: 99%

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Role of PRY-1/Axin in heterochronic miRNA-mediated seam cell development

Mallick

Ranawade

Gupta

2019

Preprint

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“…The APC/C becomes inactive prior to S phase entry, hence this is unlikely to be the only level of RNT-1 regulation. We considered posttranscriptional repression of rnt-1 mRNA by microRNAs (miRNAs), which are important regulators of progression through L2, and transition to the L3 stage (Abbott et al 2005;Li et al 2005;Tsialikas et al 2017). The let-7 sister miRNAs, miR-48, miR-84, and miR-241 would be candidates for rnt-1 regulation, however, removal of a putative let-7s miRNA target site from the endogenous rnt-1 3' untranslated region did not induce rnt-1 gain of function ( Fig.…”

Section: The Rnt-1/bro-1 Transcriptional Repressor Complex Promotes Smentioning

confidence: 99%

C. elegans Runx/CBFβ suppresses POP-1(TCF) to convert asymmetric to proliferative division of stem cell-like seam cells

Horst

Cravo

Woollard

et al. 2019

Preprint

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A correct balance between proliferative and asymmetric cell divisions underlies normal development, stem cell maintenance and tissue homeostasis. What determines whether cells undergo symmetric or asymmetric cell division is poorly understood. To gain insight in the mechanisms involved, we studied the stem cell-like seam cells in the Caenorhabditis elegans epidermis. Seam cells go through a reproducible pattern of asymmetric divisions, instructed by non-canonical Wnt/β-catenin asymmetry signaling, and symmetric divisions that increase the seam cell number. Using time-lapse fluorescence microscopy, we show that symmetric cell divisions maintain the asymmetric localization of Wnt/β-catenin pathway components. Observations based on lineage-specific knockout and GFP-tagging of endogenous pop-1 support the model that POP-1 TCF induces differentiation at a high nuclear level, while low nuclear POP-1 promotes seam cell self-renewal. Before symmetric division, the transcriptional regulator rnt-1 Runx and cofactor bro-1 CBFβ temporarily bypass Wnt/βcatenin asymmetry by downregulating pop-1 expression. Thereby, RNT-1/BRO-1 appears to render POP-1 below the level required for its repressor function, which converts differentiation into self-renewal. Thus, opposition between the C. elegans Runx/CBFβ and TCF stem-cell regulators controls the switch between asymmetric and symmetric seam cell division.

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“…The conserved RNA binding protein LIN-28 indirectly (indicated by the dotted line break) regulates the transcription [33] and activities [34] of let-7-family (mir-48, mir-84, mir-241) microRNAs, which inhibit the synthesis of HBL-1. LIN-28 also represses the expression of LIN-46 [17], which controls the nuclear accumulation of HBL-1.…”

Section: Figure 4 Regulation Of Gene Activity Through Microrna-mediamentioning

confidence: 99%

Regulation of nuclear-cytoplasmic partitioning by thelin-28-lin-46pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression inC. elegans

Ilbay

Ambros

2019

Preprint

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MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In C. elegans, the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2) stage cell-fate, and the let-7-family microRNAs temporally down-regulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to let-7-family microRNAs, the conserved RNA binding protein LIN-28 and its downstream gene lin-46, also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the lin-28-lin-46 pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the lin-28-lin-46 pathway is independent of the let-7/lin-4 microRNA complementary sites (LCSs) in the hbl-1 3'UTR, and involves a stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that the robust progression from L2 to L3 cell-fates depends on the combination of two distinct modes of HBL-1 down-regulation: decreased synthesis of HBL-1 via let-7-family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the lin-28-lin-46 pathway. Like HBL-1, many microRNA targets are transcription factors (TFs); and cooperation between regulation of nuclear accumulation and microRNA-mediated control of synthesis rate may be required to increase the precision of or confer robustness to down-regulation of these microRNA target TFs, which can be critical to achieve the optimal phenotypes.

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

Cited by 18 publications

References 44 publications

Role of PRY-1/Axin in heterochronic miRNA-mediated seam cell development

Role of PRY-1/Axin in heterochronic miRNA-mediated seam cell development

C. elegans Runx/CBFβ suppresses POP-1(TCF) to convert asymmetric to proliferative division of stem cell-like seam cells

Regulation of nuclear-cytoplasmic partitioning by thelin-28-lin-46pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression inC. elegans

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