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Caenorhabditis Elegans Alg-1 Antimorphic Mutations Uncover Functions For Argonaute In Microrna Guide Strand Selection And Passenger Strand Disposal, Anna Y. Zinovyeva, Isana Veksler-Lublinsky, Ajay A. Vashisht, James A. Wohlschlegel, Victor R. Ambros
Caenorhabditis Elegans Alg-1 Antimorphic Mutations Uncover Functions For Argonaute In Microrna Guide Strand Selection And Passenger Strand Disposal, Anna Y. Zinovyeva, Isana Veksler-Lublinsky, Ajay A. Vashisht, James A. Wohlschlegel, Victor R. Ambros
Victor R. Ambros
MicroRNAs are regulators of gene expression whose functions are critical for normal development and physiology. We have previously characterized mutations in a Caenorhabditis elegans microRNA-specific Argonaute ALG-1 (Argonaute-like gene) that are antimorphic [alg-1(anti)]. alg-1(anti) mutants have dramatically stronger microRNA-related phenotypes than animals with a complete loss of ALG-1. ALG-1(anti) miRISC (microRNA induced silencing complex) fails to undergo a functional transition from microRNA processing to target repression. To better understand this transition, we characterized the small RNA and protein populations associated with ALG-1(anti) complexes in vivo. We extensively characterized proteins associated with wild-type and mutant ALG-1 and found that the mutant …
Robust Distal Tip Cell Pathfinding In The Face Of Temperature Stress Is Ensured By Two Conserved Micrornas In Caenorhabditis Elegans, Samantha L. Burke, Molly Hammell, Victor R. Ambros
Robust Distal Tip Cell Pathfinding In The Face Of Temperature Stress Is Ensured By Two Conserved Micrornas In Caenorhabditis Elegans, Samantha L. Burke, Molly Hammell, Victor R. Ambros
Victor R. Ambros
Biological robustness, the ability of an organism to maintain a steady-state output as genetic or environmental inputs change, is critical for proper development. MicroRNAs have been implicated in biological robustness mechanisms through their post-transcriptional regulation of genes and gene networks. Previous research has illustrated examples of microRNAs promoting robustness as part of feedback loops and genetic switches and by buffering noisy gene expression resulting from environmental and/or internal changes. Here we show that the evolutionarily conserved microRNAs mir-34 and mir-83 (homolog of mammalian mir-29) contribute to the robust migration pattern of the distal tip cells in Caenorhabditis elegans by specifically …
Inhibiting Mirna In Caenorhabditis Elegans Using A Potent And Selective Antisense Reagent, Genhua Zheng, Victor R. Ambros, Wen-Hong Li
Inhibiting Mirna In Caenorhabditis Elegans Using A Potent And Selective Antisense Reagent, Genhua Zheng, Victor R. Ambros, Wen-Hong Li
Victor R. Ambros
BACKGROUND: Antisense reagents can serve as efficient and versatile tools for studying gene function by inhibiting nucleic acids in vivo. Antisense reagents have particular utility for the experimental manipulation of the activity of microRNAs (miRNAs), which are involved in the regulation of diverse developmental and physiological pathways in animals. Even in traditional genetic systems, such as the nematode Caenorhabditis elegans, antisense reagents can provide experimental strategies complementary to mutational approaches. Presently no antisense reagents are available for inhibiting miRNAs in the nematode C. elegans. RESULTS: We have developed a new class of fluorescently labelled antisense reagents to inhibit miRNAs in …
Mutations In Conserved Residues Of The C. Elegans Microrna Argonaute Alg-1 Identify Separable Functions In Alg-1 Mirisc Loading And Target Repression, Anna Y. Zinovyeva, Samir Bouasker, Martin J. Simard, Christopher M. Hammell, Victor R. Ambros
Mutations In Conserved Residues Of The C. Elegans Microrna Argonaute Alg-1 Identify Separable Functions In Alg-1 Mirisc Loading And Target Repression, Anna Y. Zinovyeva, Samir Bouasker, Martin J. Simard, Christopher M. Hammell, Victor R. Ambros
Victor R. Ambros
microRNAs function in diverse developmental and physiological processes by regulating target gene expression at the post-transcriptional level. ALG-1 is one of two Caenorhabditis elegans Argonautes (ALG-1 and ALG-2) that together are essential for microRNA biogenesis and function. Here, we report the identification of novel antimorphic (anti) alleles of ALG-1 as suppressors of lin-28(lf) precocious developmental phenotypes. The alg-1(anti) mutations broadly impair the function of many microRNAs and cause dosage-dependent phenotypes that are more severe than the complete loss of ALG-1. ALG-1(anti) mutant proteins are competent for promoting Dicer cleavage of microRNA precursors and for associating with and stabilizing microRNAs. However, …
Caenorhabditis Elegans Micrornas Of The Let-7 Family Act In Innate Immune Response Circuits And Confer Robust Developmental Timing Against Pathogen Stress, Zhiji Ren, Victor R. Ambros
Caenorhabditis Elegans Micrornas Of The Let-7 Family Act In Innate Immune Response Circuits And Confer Robust Developmental Timing Against Pathogen Stress, Zhiji Ren, Victor R. Ambros
Victor R. Ambros
Animals maintain their developmental robustness against natural stresses through numerous regulatory mechanisms, including the posttranscriptional regulation of gene expression by microRNAs (miRNAs). Caenorhabditis elegans miRNAs of the let-7 family (let-7-Fam) function semiredundantly to confer robust stage specificity of cell fates in the hypodermal seam cell lineages. Here, we show reciprocal regulatory interactions between let-7-Fam miRNAs and the innate immune response pathway in C. elegans. Upon infection of C. elegans larvae with the opportunistic human pathogen Pseudomonas aeruginosa, the developmental timing defects of certain let-7-Fam miRNA mutants are enhanced. This enhancement is mediated by the p38 MAPK innate immune pathway acting …
Effect Of Life History On Microrna Expression During C. Elegans Development, Xantha Karp, Molly Hammell, Maria C. Ow, Victor R. Ambros
Effect Of Life History On Microrna Expression During C. Elegans Development, Xantha Karp, Molly Hammell, Maria C. Ow, Victor R. Ambros
Victor R. Ambros
Animals have evolved mechanisms to ensure the robustness of developmental outcomes to changing environments. MicroRNA expression may contribute to developmental robustness because microRNAs are key post-transcriptional regulators of developmental gene expression and can affect the expression of multiple target genes. Caenorhabditis elegans provides an excellent model to study developmental responses to environmental conditions. In favorable environments, C. elegans larvae develop rapidly and continuously through four larval stages. In contrast, in unfavorable conditions, larval development may be interrupted at either of two diapause stages: The L1 diapause occurs when embryos hatch in the absence of food, and the dauer diapause occurs …
A Feedback Circuit Involving Let-7-Family Mirnas And Daf-12 Integrates Environmental Signals And Developmental Timing In Caenorhabditis Elegans, Christopher M. Hammell, Xantha Karp, Victor R. Ambros
A Feedback Circuit Involving Let-7-Family Mirnas And Daf-12 Integrates Environmental Signals And Developmental Timing In Caenorhabditis Elegans, Christopher M. Hammell, Xantha Karp, Victor R. Ambros
Victor R. Ambros
Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 larvae can enter the developmentally quiescent, stress-resistant dauer larva stage, enabling them to survive for prolonged periods before completing development. A specific progression of cell division and differentiation events occurs with fidelity during the larval stages, regardless of whether an animal undergoes continuous or dauer-interrupted development. The temporal patterning of developmental events is controlled by the heterochronic genes, whose products …
Interacting Endogenous And Exogenous Rnai Pathways In Caenorhabditis Elegans., Rosalind C. Lee, Christopher M. Hammell, Victor R. Ambros
Interacting Endogenous And Exogenous Rnai Pathways In Caenorhabditis Elegans., Rosalind C. Lee, Christopher M. Hammell, Victor R. Ambros
Victor R. Ambros
C. elegans contains numerous small RNAs of ~21-24 nt in length. The microRNAs (miRNAs) are small noncoding RNAs produced by DCR-1- and ALG-dependent processing of self-complementary hairpin transcripts. Endogenous small interfering RNAs (endo-siRNAs), associated with ongoing silencing of protein-coding genes in normal worms, are produced by mechanisms that involve DCR-1 but, unlike miRNAs, also involve RDE-2, RDE-3, RDE-4, RRF-1, and RRF-3. The tiny noncoding (tncRNAs) are similar to endo-siRNAs in their biogenesis except that they are derived from noncoding sequences. These endo-siRNA- and tncRNA-based endogenous RNAi pathways involve some components, including DCR-1 and RDE-4, that are shared with exogenous RNAi, …
The Caenorhabditis Elegans Heterochronic Regulator Lin-14 Is A Novel Transcription Factor That Controls The Developmental Timing Of Transcription From The Insulin/Insulin-Like Growth Factor Gene Ins-33 By Direct Dna Binding., Marta Hristova, Darcy Birse, Yang Hong, Victor R. Ambros
The Caenorhabditis Elegans Heterochronic Regulator Lin-14 Is A Novel Transcription Factor That Controls The Developmental Timing Of Transcription From The Insulin/Insulin-Like Growth Factor Gene Ins-33 By Direct Dna Binding., Marta Hristova, Darcy Birse, Yang Hong, Victor R. Ambros
Victor R. Ambros
A temporal gradient of the novel nuclear protein LIN-14 specifies the timing and sequence of stage-specific developmental events in Caenorhabditis elegans. The profound effects of lin-14 mutations on worm development suggest that LIN-14 directly or indirectly regulates stage-specific gene expression. We show that LIN-14 can associate with chromatin in vivo and has in vitro DNA binding activity. A bacterially expressed C-terminal domain of LIN-14 was used to select DNA sequences that contain a putative consensus binding site from a pool of randomized double-stranded oligonucleotides. To identify candidates for genes directly regulated by lin-14, we employed DNA microarray hybridization to compare …
Structure And Function Analysis Of Lin-14, A Temporal Regulator Of Postembryonic Developmental Events In Caenorhabditis Elegans, Yang Hong, Rosalind C. Lee, Victor R. Ambros
Structure And Function Analysis Of Lin-14, A Temporal Regulator Of Postembryonic Developmental Events In Caenorhabditis Elegans, Yang Hong, Rosalind C. Lee, Victor R. Ambros
Victor R. Ambros
During postembryonic development of Caenorhabditis elegans, the heterochronic gene lin-14 controls the timing of developmental events in diverse cell types. Three alternative lin-14 transcripts are predicted to encode isoforms of a novel nuclear protein that differ in their amino-terminal domains. In this paper, we report that the alternative amino-terminal domains of LIN-14 are dispensable and that a carboxy-terminal region within exons 9 to 13 is necessary and sufficient for in vivo LIN-14 function. A transgene capable of expressing only one of the three alternative lin-14 gene products rescues a lin-14 null mutation and is developmentally regulated by lin-4. This shows …
Heterochronic Genes Control The Stage-Specific Initiation And Expression Of The Dauer Larva Developmental Program In Caenorhabditis Elegans, Zhongchi Liu, Victor R. Ambros
Heterochronic Genes Control The Stage-Specific Initiation And Expression Of The Dauer Larva Developmental Program In Caenorhabditis Elegans, Zhongchi Liu, Victor R. Ambros
Victor R. Ambros
We report that a stage-specific developmental program, dauer larva formation, is temporally regulated by four heterochronic genes, lin-4, lin-14, lin-28, and lin-29. The effects of mutations in these four genes on dauer larva formation have revealed that they regulate two different processes of dauer larva formation: (1) a decision specifying the larval stage at which dauer larva development initiates, and (2) the specialized differentiation of hypodermal cells during dauer larva morphogenesis. Epistasis analysis has suggested a model in which lin-4 negatively regulates lin-14, and the resulting temporal decrease in lin-14 activity specifies the stage of dauer larva initiation. Our results …
The Lin-14 Locus Of Caenorhabditis Elegans Controls The Time Of Expression Of Specific Postembryonic Developmental Events, Victor R. Ambros, H. Robert Horvitz
The Lin-14 Locus Of Caenorhabditis Elegans Controls The Time Of Expression Of Specific Postembryonic Developmental Events, Victor R. Ambros, H. Robert Horvitz
Victor R. Ambros
The lin-14 locus of Caenorhabditis elegans plays an important role in specifying the normal timing and sequence of developmental events in the lateral hypodermal cell lineages. The results of gene dosage, complementation, and temperature-shift experiments indicate that the fates expressed by cells at successive stages of these cell lineages are specified by the level of lin-14 activity and that lin-14 acts at multiple times during development to control stage-specific choices of cell fate. Our observations suggest that during normal development a reduction in the level of lin-14 gene function causes the sequential expression of stage-specific cell fates.