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LIN-12/Notch activation leads to microRNA-mediated down-regulation of Vav in C. elegans.

ABSTRACT: Cell-cell interactions and cross-talk between signaling pathways specify Caenorhabditis elegans vulval precursor cells (VPCs) to adopt a spatial pattern: a central "1 degrees " VPC, in which epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) activity is high and LIN-12/Notch activity is low, flanked by two "2 degrees " VPCs, in which LIN-12/Notch activity is high and EGFR-MAPK activity is low. Here, we identify a microRNA gene, mir-61, as a direct transcriptional target of LIN-12 and show that expression of mir-61 promotes the 2 degrees fate. We also identify vav-1, the ortholog of the Vav oncogene, as a target of mir-61, and show that down-regulation of VAV-1 promotes lin-12 activity in specifying the 2 degrees fate. Our results suggest that lin-12, mir-61, and vav-1 form a feedback loop that helps maximize lin-12 activity in the presumptive 2 degrees VPCs.

SUBMITTER: Yoo AS

PROVIDER: S-EPMC3010395 | biostudies-other | 2005 Nov

REPOSITORIES: biostudies-other

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LIN-12/Notch activation leads to microRNA-mediated down-regulation of Vav in C. elegans.

Yoo Andrew S AS Greenwald Iva I

Science (New York, N.Y.) 20051020 5752

Cell-cell interactions and cross-talk between signaling pathways specify Caenorhabditis elegans vulval precursor cells (VPCs) to adopt a spatial pattern: a central "1 degrees " VPC, in which epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) activity is high and LIN-12/Notch activity is low, flanked by two "2 degrees " VPCs, in which LIN-12/Notch activity is high and EGFR-MAPK activity is low. Here, we identify a microRNA gene, mir-61, as a direct transcriptional tar ...[more]

PMID: 16239437

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OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development.

Project description:Notch signaling is critical for cell fate decisions during development. Caenorhabditis elegans and vertebrate Notch ligands are more diverse than classical Drosophila Notch ligands, suggesting possible functional complexities. Here, we describe a developmental role in Notch signaling for OSM-11, which has been previously implicated in defecation and osmotic resistance in C. elegans. We find that complete loss of OSM-11 causes defects in vulval precursor cell (VPC) fate specification during vulval development consistent with decreased Notch signaling. OSM-11 is a secreted, diffusible protein that, like previously described C. elegans Delta, Serrate, and LAG-2 (DSL) ligands, can interact with the lineage defective-12 (LIN-12) Notch receptor extracellular domain. Additionally, OSM-11 and similar C. elegans proteins share a common motif with Notch ligands from other species in a sequence defined here as the Delta and OSM-11 (DOS) motif. osm-11 loss-of-function defects in vulval development are exacerbated by loss of other DOS-motif genes or by loss of the Notch ligand DSL-1, suggesting that DOS-motif and DSL proteins act together to activate Notch signaling in vivo. The mammalian DOS-motif protein Deltalike1 (DLK1) can substitute for OSM-11 in C. elegans development, suggesting that DOS-motif function is conserved across species. We hypothesize that C. elegans OSM-11 and homologous proteins act as coactivators for Notch receptors, allowing precise regulation of Notch receptor signaling in developmental programs in both vertebrates and invertebrates.

| S-EPMC2504490 | biostudies-literature

LIN-12/Notch Regulates GABA Signaling at the Caenorhabditis elegans Neuromuscular Junction.

Project description:The role of Notch signaling in cell-fate decisions has been studied extensively; however, this pathway is also active in adult tissues, including the nervous system. Notch signaling modulates a wide range of behaviors and processes of the nervous system in the nematode Caenorhabditis elegans, but there is no evidence for Notch signaling directly altering synaptic strength. Here, we demonstrate Notch-mediated regulation of synaptic activity at the C. elegans neuromuscular junction (NMJ). For this, we used aldicarb, an inhibitor of the enzyme acetylcholinesterase, and assessed paralysis rates of animals with altered Notch signaling. Notch receptors LIN-12 and GLP-1 are required for normal NMJ function; they regulate NMJ activity in an opposing fashion. Complete loss of LIN-12 skews the excitation/inhibition balance at the NMJ toward increased activity, whereas partial loss of GLP-1 has the opposite effect. Specific Notch ligands and co-ligands are also required for proper NMJ function. The role of LIN-12 is independent of cell-fate decisions; manipulation of LIN-12 signaling through RNAi knockdown or overexpression of the co-ligand OSM-11 after development alters NMJ activity. We demonstrate that LIN-12 modulates GABA signaling in this paradigm, as loss of GABA signaling suppresses LIN-12 gain-of-function defects. Further analysis, in vivo and in silico, suggests that LIN-12 may modulate transcription of the GABAB receptor GBB-2 Our findings confirm a non-developmental role for the LIN-12/Notch receptor in regulating synaptic signaling and identify the GABAB receptor GBB-2 as a potential Notch transcriptional target in the C. elegans nervous system.

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Re-programming of C. elegans male epidermal precursor fates by Wnt, Hox, and LIN-12/Notch activities.

Project description:In Caenorhabditiselegans males, different subsets of ventral epidermal precursor (Pn.p) cells adopt distinct fates in a position-specific manner: three posterior cells, P(9-11).p, comprise the hook sensillum competence group (HCG) with three potential fates (1 degrees , 2 degrees , or 3 degrees ), while eight anterior cells, P(1-8).p, fuse with the hyp7 epidermal syncytium. Here we show that activation of the canonical BAR-1 beta-catenin pathway of Wnt signaling alters the competence of P(3-8).p and specifies ectopic HCG-like fates. This fate transformation requires the Hox gene mab-5. In addition, misexpression of mab-5 in P(1-8).p is sufficient to establish HCG competence among these cells, as well as to generate ectopic HCG fates in combination with LIN-12 or EGF signaling. While increased Wnt signaling induces predominantly 1 degrees HCG fates, increased LIN-12 or EGF signaling in combination with MAB-5 overexpression promotes 2 degrees HCG fates in anterior Pn.p cells, suggesting distinctive functions of Wnt, LIN-12, and EGF signaling in specification of HCG fates. Lastly, wild-type mab-5 function is necessary for normal P(9-11).p fate specification, indicating that regulation of ectopic HCG fate formation revealed in anterior Pn.p cells reflect mechanisms of pattern formation during normal hook development.

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Caenorhabditis elegans histone deacetylase hda-1 is required for morphogenesis of the vulva and LIN-12/Notch-mediated specification of uterine cell fates.

Project description:Chromatin modification genes play crucial roles in development and disease. In Caenorhabditis elegans, the class I histone deacetylase family member hda-1, a component of the nucleosome remodeling and deacetylation complex, has been shown to control cell proliferation. We recovered hda-1 in an RNA interference screen for genes involved in the morphogenesis of the egg-laying system. We found that hda-1 mutants have abnormal vulva morphology and vulval-uterine connections (i.e., no uterine-seam cell). We characterized the vulval defects by using cell fate-specific markers and found that hda-1 is necessary for the specification of all seven vulval cell types. The analysis of the vulval-uterine connection defect revealed that hda-1 is required for the differentiation of the gonadal anchor cell (AC), which in turn induces ventral uterine granddaughters to adopt π fates, leading to the formation of the uterine-seam cell. Consistent with these results, hda-1 is expressed in the vulva and AC. A search for hda-1 target genes revealed that fos-1 (fos proto-oncogene family) acts downstream of hda-1 in vulval cells, whereas egl-43 (evi1 proto-oncogene family) and nhr-67 (tailless homolog, NHR family) mediate hda-1 function in the AC. Furthermore, we showed that AC expression of hda-1 plays a crucial role in the regulation of the lin-12/Notch ligand lag-2 to specify π cell fates. These results demonstrate the pivotal role of hda-1 in the formation of the vulva and the vulval-uterine connection. Given that hda-1 homologs are conserved across the phyla, our findings are likely to provide a better understanding of HDAC1 function in development and disease.

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Autoregulation of lin-4 microRNA transcription by RNA activation (RNAa) in C. elegans.

Project description:The conserved lin-4 microRNA (miRNA) regulates the proper timing of stem cell fate decisions in C. elegans by regulating stemness genes such as lin-14 and lin-28. (1)(-) (3) While lin-4 is upregulated toward the end of the first larval stage and functions as an essential developmental timing "switch", little is known about how lin-4 expression is regulated. (4) Here we show that in C. elegans hypodermal seam cells, transcription of lin-4 is positively regulated by lin-4 itself. In these cells, lin-4 activates its own transcription through a conserved lin-4-complementary element (LCE) in its promoter. We further show that lin-4 is required to recruit RNA polymerase II to its own promoter, and that lin-4 overexpression is sufficient for autoactivation. Finally, we show that a protein complex specifically binds the LCE in vitro, and that mutations that abolish this binding also reduce the in vivo expression of a plin-4:GFP reporter. Thus, we describe the first in vivo evidence of RNA activation (RNAa) by an endogenous miRNA, and provide new insights into an elegant autoregulatory mechanism that ensures the proper timing of stem cell fate decisions in development.

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Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans.

Project description:Presenilin is an essential component of the LIN-12/Notch signaling pathway and also plays a critical role in the genesis of Alzheimer's disease. Previously, a screen for suppressors of the egg-laying defective phenotype caused by partial loss of presenilin activity in Caenorhabditis elegans identified a number of new spr genes that are potentially involved in the regulation of LIN-12/Notch signaling or presenilin activity. Here we report the molecular identity of two spr genes, spr-1 and spr-5. Our genetic analysis indicates that loss of spr-1 elevates lin-12/Notch gene activity in many different cell fate decisions, suggesting that spr-1 is a negative regulator of LIN-12/Notch signaling. Sequence analysis revealed that spr-1 is an ortholog of human CoREST, a known corepressor. SPR-1 is localized to the nucleus and acts in a cell-autonomous manner; furthermore, human CoREST can substitute for SPR-1 in C. elegans. We also show that spr-5 encodes a homolog of p110b, another known member of the CoREST corepressor complex. Our results suggest that the CoREST corepressor complex might be functionally conserved in worms, and we discuss the potential role of SPR-1 and SPR-5 in the repression of transcription of genes involved in, or downstream of, LIN-12/Notch signal transduction.

| S-EPMC187465 | biostudies-literature

Determinants in the LIN-12/Notch Intracellular Domain That Govern Its Activity and Stability During Caenorhabditis elegans Vulval Development.

Project description:Upon ligand binding, the LIN-12/Notch intracellular domain is released from its transmembrane tether to function in a nuclear complex to activate transcription of target genes. During Caenorhabditis elegans vulval development, LIN-12/Notch is activated by ligand in two of six multipotential Vulval Precursor Cells (VPCs), specifying the "2o vulval fate" and descendants that contribute to the vulva. If LIN-12 is ectopically activated in other VPCs, they also adopt the 2o fate, dividing to produce extra vulval cells and resulting in a "Multivulva" phenotype. Here, we identify determinants in the LIN-12 intracellular domain that govern its activity and stability during C. elegans vulval development; we assayed activity of mutant forms based on their ability to cause a Multivulva phenotype and stability using a GFP tag to visualize their accumulation. Our analysis has revealed that, while the ubiquitin ligase SEL-10/Fbw7 promotes LIN-12(intra) downregulation in VPCs, there is a distinct mechanism for downregulation of LIN-12(intra) in VPC descendants. Our analysis also revealed that LIN-12(intra) must be in the nuclear complex to be regulated appropriately in VPCs and their descendants, and that the structure or conformation of the carboxy terminal region influences the stability as well. Although activity and stability are generally well-correlated, exceptions where they are uncoupled suggests that there may be roles for the carboxy terminal region and sel-10 that are independent of their roles in regulating LIN-12(intra) stability.

| S-EPMC5100865 | biostudies-other

LIN-14 inhibition of LIN-12 contributes to precision and timing of C. elegans vulval fate patterning.

Project description:Studies of C. elegans vulval development have illuminated mechanisms underlying cell fate specification and elucidated intercellular signaling pathways [1]. The vulval precursor cells (VPCs) are spatially patterned during the L3 stage by the EGFR-Ras-MAPK-mediated inductive signal and the LIN-12/Notch-mediated lateral signal. The pattern is both precise and robust [2] because of crosstalk between these pathways [3]. Signaling is also regulated temporally, because constitutive activation of the spatial patterning pathways does not alter the timing of VPC fate specification [4, 5]. The heterochronic genes, including the microRNA lin-4 and its target lin-14, constitute a temporal control mechanism used in different contexts [6-8]. We find that lin-4 specifically controls the activity of LIN-12/Notch through lin-14, but not other known targets, and that persistent lin-14 blocks LIN-12 activity without interfering with the key events of LIN-12/Notch signal transduction. In the L2 stage, there is sufficient lin-14 activity to inhibit constitutive lin-12. Our results suggest that lin-4 and lin-14 contribute to spatial patterning through temporal gating of LIN-12. We propose that in the L2 stage, lin-14 sets a high threshold for LIN-12 activation to help prevent premature activation of LIN-12 by ligands expressed in other cells in the vicinity, thereby contributing to the precision and robustness of VPC fate patterning.

| S-EPMC3322352 | biostudies-literature

LIN-42, the Caenorhabditis elegans PERIOD homolog, negatively regulates microRNA transcription.

Project description:During C. elegans development, microRNAs (miRNAs) function as molecular switches that define temporal gene expression and cell lineage patterns in a dosage-dependent manner. It is critical, therefore, that the expression of miRNAs be tightly regulated so that target mRNA expression is properly controlled. The molecular mechanisms that function to optimize or control miRNA levels during development are unknown. Here we find that mutations in lin-42, the C. elegans homolog of the circadian-related period gene, suppress multiple dosage-dependent miRNA phenotypes including those involved in developmental timing and neuronal cell fate determination. Analysis of mature miRNA levels in lin-42 mutants indicates that lin-42 functions to attenuate miRNA expression. Through the analysis of transcriptional reporters, we show that the upstream cis-acting regulatory regions of several miRNA genes are sufficient to promote highly dynamic transcription that is coupled to the molting cycles of post-embryonic development. Immunoprecipitation of LIN-42 complexes indicates that LIN-42 binds the putative cis-regulatory regions of both non-coding and protein-coding genes and likely plays a role in regulating their transcription. Consistent with this hypothesis, analysis of miRNA transcriptional reporters in lin-42 mutants indicates that lin-42 regulates miRNA transcription. Surprisingly, strong loss-of-function mutations in lin-42 do not abolish the oscillatory expression patterns of lin-4 and let-7 transcription but lead to increased expression of these genes. We propose that lin-42 functions to negatively regulate the transcriptional output of multiple miRNAs and mRNAs and therefore coordinates the expression levels of genes that dictate temporal cell fate with other regulatory programs that promote rhythmic gene expression.

| S-EPMC4102445 | biostudies-literature

Integration of EGFR and LIN-12/Notch Signaling by LIN-1/Elk1, the Cdk8 Kinase Module, and SUR-2/Med23 in Vulval Precursor Cell Fate Patterning in <i>Caenorhabditis elegans</i>.

Project description:Six initially equivalent, multipotential Vulval Precursor Cells (VPCs) in Caenorhabditis elegans adopt distinct cell fates in a precise spatial pattern, with each fate associated with transcription of different target genes. The pattern is centered on a cell that adopts the "1°" fate through Epidermal Growth Factor Receptor (EGFR) activity, and produces a lateral signal composed of ligands that activate LIN-12/Notch in the two flanking VPCs to cause them to adopt "2°" fate. Here, we investigate orthologs of a transcription complex that acts in mammalian EGFR signaling-lin-1/Elk1, sur-2/Med23, and the Cdk8 Kinase module (CKM)-previously implicated in aspects of 1° fate in C. elegans and show they act in different combinations for different processes for 2° fate. When EGFR is inactive, the CKM, but not SUR-2, helps to set a threshold for LIN-12/Notch activity in all VPCs. When EGFR is active, all three factors act to resist LIN-12/Notch, as revealed by the reduced ability of ectopically-activated LIN-12/Notch to activate target gene reporters. We show that overcoming this resistance in the 1° VPC leads to repression of lateral signal gene reporters, suggesting that resistance to LIN-12/Notch helps ensure that P6.p becomes a robust source of the lateral signal. In addition, we show that sur-2/Med23 and lin-1/Elk1, and not the CKM, are required to promote endocytic downregulation of LIN-12-GFP in the 1° VPC. Finally, our analysis using cell fate reporters reveals that both EGFR and LIN-12/Notch signal transduction pathways are active in all VPCs in lin-1/Elk1 mutants, and that lin-1/Elk1 is important for integrating EGFR and lin-12/Notch signaling inputs in the VPCs so that the proper gene complement is transcribed.

| S-EPMC5714460 | biostudies-literature

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