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• W2945202325 abstract "•Ascr#5 corrects heterochronic cell-fate defects of daf-12(rh61) mutants•Ascarosides reduce the developmental reliance on let-7 family microRNAs•DAF-12 mediates an L2d rewiring of networks controlling temporal cell fates•Developmental progression and temporal cell fates are coordinately regulated Adverse environmental conditions can affect rates of animal developmental progression and lead to temporary developmental quiescence (diapause), exemplified by the dauer larva stage of the nematode Caenorhabditis elegans (C. elegans). Remarkably, patterns of cell division and temporal cell-fate progression in C. elegans larvae are not affected by changes in developmental trajectory. However, the underlying physiological and gene regulatory mechanisms that ensure robust developmental patterning despite substantial plasticity in developmental progression are largely unknown. Here, we report that diapause-inducing pheromones correct heterochronic developmental cell lineage defects caused by insufficient expression of let-7 family microRNAs in C. elegans. Moreover, two conserved endocrine signaling pathways, DAF-7/TGF-β and DAF-2/Insulin, that confer on the larva diapause and non-diapause alternative developmental trajectories interact with the nuclear hormone receptor, DAF-12, to initiate and regulate a rewiring of the genetic circuitry controlling temporal cell fates. This rewiring includes engagement of certain heterochronic genes, lin-46, lin-4, and nhl-2, that are previously associated with an altered genetic program in post-diapause animals, in combination with a novel ligand-independent DAF-12 activity, to downregulate the critical let-7 family target Hunchback-like-1 (HBL-1). Our results show how pheromone or endocrine signaling pathways can coordinately regulate both developmental progression and cell-fate transitions in C. elegans larvae under stress so that the developmental schedule of cell fates remains unaffected by changes in developmental trajectory. Adverse environmental conditions can affect rates of animal developmental progression and lead to temporary developmental quiescence (diapause), exemplified by the dauer larva stage of the nematode Caenorhabditis elegans (C. elegans). Remarkably, patterns of cell division and temporal cell-fate progression in C. elegans larvae are not affected by changes in developmental trajectory. However, the underlying physiological and gene regulatory mechanisms that ensure robust developmental patterning despite substantial plasticity in developmental progression are largely unknown. Here, we report that diapause-inducing pheromones correct heterochronic developmental cell lineage defects caused by insufficient expression of let-7 family microRNAs in C. elegans. Moreover, two conserved endocrine signaling pathways, DAF-7/TGF-β and DAF-2/Insulin, that confer on the larva diapause and non-diapause alternative developmental trajectories interact with the nuclear hormone receptor, DAF-12, to initiate and regulate a rewiring of the genetic circuitry controlling temporal cell fates. This rewiring includes engagement of certain heterochronic genes, lin-46, lin-4, and nhl-2, that are previously associated with an altered genetic program in post-diapause animals, in combination with a novel ligand-independent DAF-12 activity, to downregulate the critical let-7 family target Hunchback-like-1 (HBL-1). Our results show how pheromone or endocrine signaling pathways can coordinately regulate both developmental progression and cell-fate transitions in C. elegans larvae under stress so that the developmental schedule of cell fates remains unaffected by changes in developmental trajectory. Despite the vast complexity of animal development, developmental processes are remarkably robust in the face of environment and physiological stresses. Multicellular animals develop from a single cell through a temporal and spatial elaboration of events that include cell division, differentiation, migration, and apoptosis. Early developmental cell lineages rapidly diverge functionally and spatially and continue to follow distinct paths toward building diverse parts of the animal body. Marvelously, the sequence and synchrony of these increasingly complex programs of cell-fate progression are precisely coordinated, regardless of various environmental and physiological stresses that the animal may encounter in its natural environment. The nematode C. elegans develops through four larval stages, each of which consists of an invariant set of characteristic developmental events [1Sulston J.E. Horvitz H.R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans.Dev. Biol. 1977; 56: 110-156Crossref PubMed Scopus (2473) Google Scholar]. During larval development, stem cells and blast cells divide and progressively produce progeny cells with defined stage-specific fates. The timing of cell-fate transitions within individual postembryonic cell lineages is regulated by genes of the heterochronic pathway, whose products include cell-fate-determinant transcription factors as well as microRNAs (miRNAs) and other regulators of these transcription factors [2Ambros V. Horvitz H.R. Heterochronic mutants of the nematode Caenorhabditis elegans.Science. 1984; 226: 409-416Crossref PubMed Scopus (576) Google Scholar, 3Ambros V. MicroRNAs and developmental timing.Curr. Opin. Genet. Dev. 2011; 21: 511-517Crossref PubMed Scopus (227) Google Scholar]. In mutants defective in the activity of one or more heterochronic genes, the synchrony between cell fates and developmental stages is lost in certain cell lineages, which results in dissonance in the relative timing of developmental events across the animal and consequently morphological abnormalities. During C. elegans larval development, lateral hypodermal stem cells (“seam cells”) express stage-specific proliferative or self-renewal behavior (Figure 1A). Particularly, while seam cells divide asymmetrically at each larval stage (L1–L4), giving rise to a new seam cell and a differentiating hypodermal (hyp7) cell, at the L2 stage, certain seam cells also undergo a single round of symmetric cell division, resulting in an increase in the number of seam cells on each side of the animal from ten to sixteen. This L2-specific proliferative cell fate is driven by a transcription factor, HBL-1, which specifies expression of the L2 cell fate and also prevents the expression of the L3 cell fates [4Lin S.Y. Johnson S.M. Abraham M. Vella M.C. Pasquinelli A. Gamberi C. Gottlieb E. Slack F.J. The C elegans hunchback homolog, hbl-1, controls temporal patterning and is a probable microRNA target.Dev. Cell. 2003; 4: 639-650Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 5Abrahante J.E. Daul A.L. Li M. Volk M.L. Tennessen J.M. Miller E.A. Rougvie A.E. The Caenorhabditis elegans hunchback-like gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs.Dev. Cell. 2003; 4: 625-637Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar]. Therefore, in order to allow progression to L3 cell fates, HBL-1 must be downregulated by the end of the L2 stage. If HBL-1 is not properly downregulated, for example in mutants defective in upstream regulatory genes, seam cells inappropriately execute L2 cell fates at later stages, resulting in an enlarged and developmentally retarded population of seam cells in adult worms. Three let-7 family miRNAs (mir-48, mir-84, and mir-241) are redundantly required for proper temporal downregulation of HBL-1 [6Abbott A.L. Alvarez-Saavedra E. Miska E.A. Lau N.C. Bartel D.P. Horvitz H.R. Ambros V. The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans.Dev. Cell. 2005; 9: 403-414Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar]. Larvae lacking all three let-7 family miRNAs reiterate L2 cell fates in later stages of development. The degree of reiteration, hence the severity of the phenotype, varies depending on genetic and environmental factors [7Ren Z. Ambros V.R. Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress.Proc. Natl. Acad. Sci. USA. 2015; 112: E2366-E2375Crossref PubMed Scopus (59) Google Scholar] and can be quantified by counting the number of seam cells in young adult worms. C. elegans is a free-living nematode whose environment is prone to fluctuations between conditions that are favorable and unfavorable for completion of development [8Frézal L. Félix M.-A. C. elegans outside the Petri dish.eLife. 2015; 4https://doi.org/10.7554/eLife.05849Crossref PubMed Scopus (143) Google Scholar]. Under favorable conditions (such as abundant food), C. elegans larvae develop rapidly and continuously progress through the four larval stages to the adult (Figure 1B, rapid). However, when the conditions are not favorable (for example, in the face of declining resources owing to high population density), the larva at the end of the L2 stage can elect to enter a developmentally arrested diapause, called the dauer larva, which is non-feeding, stress resistant, and long lived [9Hu P.J. Dauer.in: Riddle D.L. WormBook, WormBook, 2007https://doi.org/10.1895/wormbook.1.144.1Crossref Scopus (273) Google Scholar]. When conditions improve, the dauer larva resumes development to the reproductive adult (Figure 1B, post-dauer). The DAF-7/TGF-β and DAF-2/insulin endocrine signaling pathways are the two major signaling pathways that regulate C. elegans dauer larva diapause. These two pathways act in parallel to integrate information about population density and nutritional status by co-modulating the biosynthesis of the dafachronic acid (DA) hormone. DA is the ligand of a nuclear hormone receptor, DAF-12, which opposes dauer formation when it is DA-bound and forms a repressor complex with DIN-1S and promotes dauer formation when it is unliganded (Figure 1C) [10Fielenbach N. Antebi A. C. elegans dauer formation and the molecular basis of plasticity.Genes Dev. 2008; 22: 2149-2165Crossref PubMed Scopus (362) Google Scholar]. The order and sequence of temporal cell fates in the various C. elegans larval cell lineages are robustly maintained regardless of developmental trajectory: for example, blast cells properly transition from L2 to L3 fates whether the larva develops rapidly and continuously or instead traverses dauer diapause, which imposes a lengthy (even months-long) interruption of the L2 to L3 transition (Figures 1A and 1B). Interestingly, cell-fate transition defects of many heterochronic mutants are modified (either suppressed or enhanced) when larval development is interrupted by dauer diapause, suggesting that the genetic regulatory pathways regulating temporal cell-fate progression are modified depending on whether the animal develops continuously versus undergoes dauer-interrupted development [11Liu Z. Ambros V. Alternative temporal control systems for hypodermal cell differentiation in Caenorhabditis elegans.Nature. 1991; 350: 162-165Crossref PubMed Scopus (42) Google Scholar, 12Euling S. Ambros V. Reversal of cell fate determination in Caenorhabditis elegans vulval development.Development. 1996; 122: 2507-2515PubMed Google Scholar, 13Karp X. Ambros V. Dauer larva quiescence alters the circuitry of microRNA pathways regulating cell fate progression in C. elegans.Development. 2012; 139: 2177-2186Crossref PubMed Scopus (30) Google Scholar]. The mechanisms by which temporal cell-fate specification pathways are modified in association with the dauer larva trajectory are poorly understood, especially with regards to how modifications to the regulatory networks controlling temporal cell-fate transitions may be coupled to particular steps in the specification and/or execution of the dauer larva diapause trajectory. Of particular interest is the question of whether and how the dauer-promoting signals that are monitored by L1 and L2d larvae might act prior to dauer commitment to directly modify gene regulatory mechanisms controlling temporal cell-fate transitions. To investigate the impact of dauer-inducing environmental and endocrine signals on the regulatory network controlling temporal cell-fate transitions, we employed experimental conditions that not only induce the dauer formation program but also efficiently prevent dauer commitment. We call these conditions “L2d inducing” because the presence of both dauer-inducing and commitment-preventing conditions results in worm populations growing continuously (without dauer arrest) but where all animals traverse the lengthened bi-potential L2d stage (Figure 1B, L2d/delayed) [14Golden J.W. Riddle D.L. The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food, and temperature.Dev. Biol. 1984; 102: 368-378Crossref PubMed Scopus (417) Google Scholar, 15Avery L. A model of the effect of uncertainty on the C elegans L2/L2d decision.PLoS ONE. 2014; 9: e100580Crossref PubMed Scopus (9) Google Scholar]. We found that L2d-inducing pheromones suppress heterochronic defects caused by insufficient expression of let-7 family microRNAs, suggesting that these pheromones that enable the dauer life history option also activate a program alternative to let-7 family microRNAs in controlling stage-specific temporal cell-fate progression. We found that the two major endocrine signaling pathways that regulate dauer formation in response to pheromones and food signals, the DAF-7/TGF-β and DAF-2/Insulin, respectively, also mediate the effect of these same signals on temporal cell fates under L2d-inducing conditions. Moreover, we identified a previously undescribed ligand-independent activity of the nuclear hormone receptor DAF-12 that is responsible for activating the alternative program of cell-fate specification in the L2d. This alternative program is responsible for correcting let-7 family insufficiency phenotypes, and it requires the activities of certain heterochronic genes, lin-46, lin-4, and nhl-2, that are previously associated with an altered genetic program in post-diapause animals. This alternative program associated with L2d is coupled to a previously described reduction in the DAF-12-regulated expression of let-7 family microRNAs [16Hammell C.M. Karp X. Ambros V. A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2009; 106: 18668-18673Crossref PubMed Scopus (105) Google Scholar]. Hence, the overall L2d response is a “rewiring” program consisting two major operations: (1) repression of let-7 family microRNA expression, and (2) activation of an alternative program to downregulate the let-7 family target (Hunchback-like-1) HBL-1. Our results show that environmental signals and downstream endocrine signaling pathways are capable of coordinately regulating developmental progression and cell-fate transitions in C. elegans. We propose that this capability confers elasticity to C. elegans development, whereby the proper developmental schedule of cell fates remains unaffected by changes or uncertainties in developmental trajectory. We developed three approaches to efficiently uncouple L2d from dauer commitment and thereby produce worm populations developing continuously through the bi-potential pre-dauer L2d phase directly to the L3, without dauer arrest. In the first approach, we employed the pheromone cocktail formula described by Butcher et al. [17Butcher R.A. Ragains J.R. Kim E. Clardy J. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.Proc. Natl. Acad. Sci. USA. 2008; 105: 14288-14292Crossref PubMed Scopus (116) Google Scholar], which contains three ascaroside molecules (ascr#2, ascr#3, and ascr#5) that synergistically induce L2d and dauer arrest [17Butcher R.A. Ragains J.R. Kim E. Clardy J. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.Proc. Natl. Acad. Sci. USA. 2008; 105: 14288-14292Crossref PubMed Scopus (116) Google Scholar] (Figure S1A). At sufficiently high doses, the ascaroside cocktail can induce 100% dauer formation (Figure S1C). Previous findings showed that the presence of food can antagonize pheromones and prevent dauer formation [14Golden J.W. Riddle D.L. The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food, and temperature.Dev. Biol. 1984; 102: 368-378Crossref PubMed Scopus (417) Google Scholar]. However, it was not clear if the food signals also prevented the L2d. We observed that the presence of live bacteria food, or the presence of dafachronic acid (DA) hormone, could efficiently prevent dauer formation while not preventing the L2d, evidenced by dramatically slowed second-stage larval development. Therefore, to obtain animal populations traversing the L2d without committing to dauer arrest, we allowed larvae to develop in the presence of a combination of the ascaroside cocktail along with DA hormone [18Motola D.L. Cummins C.L. Rottiers V. Sharma K.K. Li T. Li Y. Suino-Powell K. Xu H.E. Auchus R.J. Antebi A. Mangelsdorf D.J. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans.Cell. 2006; 124: 1209-1223Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar] (Figures S1B and S1C). Our second approach also uses the ascaroside cocktail, but to eliminate the need for DA hormone, dauer-commitment-defective daf-12(rh61) mutant worms are employed. In the third approach, to genetically induce L2d, we combined daf-12(rh61) with a temperature-sensitive daf-7 mutant that mimics the L2d-inducing pheromone conditions or with a temperature-sensitive daf-2 mutant that mimics the L2d-inducing starvation conditions. Wild-type larvae robustly execute L2-stage cell fates and transition to L3-stage cell fates (thus, # of seam cell = 16 in young adult worms) regardless of developmental trajectory (Figure 2, rows 1–3). mir-48/84/241(0) triply-mutant larvae reiterate L2-stage cell fates at later stages due to prolonged HBL-1 expression, resulting in extra (>16) seam cells in young adult animals (Figure 2, row 4). We found that when mir-48/84/241(0) mutant larvae developed through L2d—induced by a combination of the ascaroside cocktail and the DA hormone—the extra seam cell phenotype was substantially (albeit partially) suppressed (Figure 2, row 4 versus 6). To compare the strength of this L2d suppression with the previously described post-dauer suppression of the let-7 family phenotypes [13Karp X. Ambros V. Dauer larva quiescence alters the circuitry of microRNA pathways regulating cell fate progression in C. elegans.Development. 2012; 139: 2177-2186Crossref PubMed Scopus (30) Google Scholar], we used the ascaroside cocktail but this time without the DA hormone. Under these conditions, mir-48/84/241(0) larvae arrested as dauers; and as described previously [13Karp X. Ambros V. Dauer larva quiescence alters the circuitry of microRNA pathways regulating cell fate progression in C. elegans.Development. 2012; 139: 2177-2186Crossref PubMed Scopus (30) Google Scholar], this resulted in complete suppression of the extra seam cell phenotype in post-dauer adults (Figure 2, row 4 versus 5). Therefore, the L2d suppression is weaker than the post-dauer suppression (Figure 2, row 6 versus 5), and unlike dauer arrest, L2d-inducing ascarosides do not completely eliminate the need for let-7 family microRNAs for proper L2-to-L3 cell-fate transition. Nonetheless, the partial suppression of the extra seam cell phenotype of let-7 family microRNAs suggests that the L2d-inducing ascarosides rewire the genetic regulatory pathway controlling temporal cell-fate progression in a way to reduce the reliance on the let-7 family microRNAs for proper L2-to-L3 cell-fate transition. The daf-12(rh61) mutation combines three important properties, which makes this mutation uniquely useful for studying the effects of L2d-inducing conditions on the regulation of temporal cell fates. These properties are as follows: (1) daf-12(rh61) animals reiterate expression of L2 cell fates owing to reduced (insufficient) let-7 family levels; (2) daf-12(rh61) larvae are unable to execute dauer larvae commitment or arrest [19Antebi A. Yeh W.H. Tait D. Hedgecock E.M. Riddle D.L. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans.Genes Dev. 2000; 14: 1512-1527Crossref PubMed Google Scholar], enabling the use of dauer-promoting conditions to obtain populations of daf-12(rh61) animals undergoing an L2d-direct-to-L3 continuous development trajectory; and (3) daf-12(rh61) animals are insensitive to the DA hormone (due to lack of the DAF-12 ligand binding domain) [18Motola D.L. Cummins C.L. Rottiers V. Sharma K.K. Li T. Li Y. Suino-Powell K. Xu H.E. Auchus R.J. Antebi A. Mangelsdorf D.J. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans.Cell. 2006; 124: 1209-1223Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 19Antebi A. Yeh W.H. Tait D. Hedgecock E.M. Riddle D.L. daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans.Genes Dev. 2000; 14: 1512-1527Crossref PubMed Google Scholar], and so the levels of let-7 family microRNAs are expected to be unresponsive to experimentally administered ascarosides, which are understood to regulate wild-type DAF-12 activity by affecting the level of DA [10Fielenbach N. Antebi A. C. elegans dauer formation and the molecular basis of plasticity.Genes Dev. 2008; 22: 2149-2165Crossref PubMed Scopus (362) Google Scholar]. We observed that the presence of exogenous ascaroside cocktail during larval development almost completely suppressed the extra seam cell phenotype of daf-12(rh61) mutants (Figure 2, row 7 versus 8). To test the possibility that an unexpected elevation in the let-7 family levels could be responsible for the suppression of the heterochronic phenotypes of daf-12(rh61) animals in the presence of the ascaroside cocktail, we quantified the levels of let-7 family microRNAs in the absence and presence of the ascarosides (Figure S2). No elevation in the levels of these microRNAs in response to the ascaroside cocktail was evident (Figure S2). Therefore, the suppression of the heterochronic phenotypes of daf-12(rh61) mutants in the presence of the ascaroside cocktail is unlikely to result from restoration of normal levels of mir-48/84/241 or an elevation of the other members of the let-7 family microRNAs (Figure S2). Similar to the ascaroside cocktail, conditional dauer-constitutive mutants of daf-7 (mimicking high ascarosides) or daf-2 (mimicking starvation) that allow continuous (L2d-to-L3 without dauer arrest) development at permissive temperatures [20Swanson M.M. Riddle D.L. Critical periods in the development of the Caenorhabditis elegans dauer larva.Dev. Biol. 1981; 84: 27-40Crossref PubMed Scopus (91) Google Scholar] almost completely suppressed the extra seam cell phenotype of daf-12(rh61) mutants (Figure 2, row 7 versus 9 or 10). These results indicate that genetically induced L2d, whether by activation of the ascaroside response pathway (daf-7(lf)) or by activating the starvation response pathway (daf-2(lf)), results in an L2d-associated rewiring of the regulatory networks controlling temporal cell-fate progression. Each of the individual ascarosides in the cocktail (ascrs#2, 3, and 5) has been shown previously to be alone sufficient to induce dauer formation, although with reduced potency compared to the combined cocktail [17Butcher R.A. Ragains J.R. Kim E. Clardy J. A potent dauer pheromone component in Caenorhabditis elegans that acts synergistically with other components.Proc. Natl. Acad. Sci. USA. 2008; 105: 14288-14292Crossref PubMed Scopus (116) Google Scholar, 21Butcher R.A. Fujita M. Schroeder F.C. Clardy J. Small-molecule pheromones that control dauer development in Caenorhabditis elegans.Nat. Chem. Biol. 2007; 3: 420-422Crossref PubMed Scopus (253) Google Scholar]. Consistent with their individual capacities to induce L2d and dauer formation, we observed that each ascaroside ascr#2, ascr#3, and ascr#5 alone could suppress the extra seam cell phenotype of daf-12(rh61) mutants (Figure S3A). In the case of ascr#2 or ascr#3 alone, the suppression was partial, while for ascr#5 alone, the suppression was similar to that of the full cocktail (Figure S3A, rows 6 to 10). ascr#5 was the most potent of the three ascarosides in terms of both percent dauer formation of wild-type larvae (Figure S3B) and suppression of the extra seam cell phenotype of daf-12(rh61) (Figure S3A, row 10 versus 8 and 9). It has been shown previously that induction of dauer formation by ascarosides involves sensing of environmental ascaroside levels by specific G-protein coupled receptors (GPCRs) expressed in chemosensory neurons, wherein they repress DAF-7/TGF-β signals [22Ren P. Lim C.S. Johnsen R. Albert P.S. Pilgrim D. Riddle D.L. Control of C. elegans larval development by neuronal expression of a TGF-beta homolog.Science. 1996; 274: 1389-1391Crossref PubMed Scopus (413) Google Scholar, 23Kim K. Sato K. Shibuya M. Zeiger D.M. Butcher R.A. Ragains J.R. Clardy J. Touhara K. Sengupta P. Two chemoreceptors mediate developmental effects of dauer pheromone in C. elegans.Science. 2009; 326: 994-998Crossref PubMed Scopus (148) Google Scholar, 24McGrath P.T. Xu Y. Ailion M. Garrison J.L. Butcher R.A. Bargmann C.I. Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes.Nature. 2011; 477: 321-325Crossref PubMed Scopus (169) Google Scholar, 25Park D. O’Doherty I. Somvanshi R.K. Bethke A. Schroeder F.C. Kumar U. Riddle D.L. Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2012; 109: 9917-9922Crossref PubMed Scopus (78) Google Scholar]. To test whether these GPCRs were also required for the suppression of the heterochronic phenotypes of daf-12(rh61) mutants, we employed mutations of srg-36 and srg-37, which encode GPCRs that are expressed in the ASI neurons and that are redundantly required for perceiving ascr#5 signal in the context of dauer induction [24McGrath P.T. Xu Y. Ailion M. Garrison J.L. Butcher R.A. Bargmann C.I. Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes.Nature. 2011; 477: 321-325Crossref PubMed Scopus (169) Google Scholar]. We observed that for srg-36(0) srg-37(0); daf-12(rh61) compound mutants, ascaroside (in this case ascr#5) failed to suppress the extra seam cell phenotype daf-12(rh61) (Figure 3A, compare row 1 versus 2 with row 3 versus 4). Moreover, we found that the TGF-β signaling effector daf-3, which is thought to function downstream of SRG-36/37, is required for the suppression of daf-12(rh61) by asaroside (Figure 3B). These results indicate that the same GPCRs that mediate dauer formation in response to asaroside are also required for mediating the effects of asaroside on temporal cell fates and support a common pathway for suppression of daf-12(rh61) by ascaroside and dauer induction, involving activation of SRG-36/37 GPCRs and the potential downstream TGF-β effector DAF-3. As shown above, genetic activation of dauer-inductive signaling by daf-7(lf) or daf-2(lf) mutations is sufficient for suppression of daf-12(rh61) (Figure 2). In the context of dauer formation, DAF-7/TGF-β primarily mediates ascaroside signaling, and DAF-2/Insulin primarily mediates assessment of nutritional status [10Fielenbach N. Antebi A. C. elegans dauer formation and the molecular basis of plasticity.Genes Dev. 2008; 22: 2149-2165Crossref PubMed Scopus (362) Google Scholar, 22Ren P. Lim C.S. Johnsen R. Albert P.S. Pilgrim D. Riddle D.L. Control of C. elegans larval development by neuronal expression of a TGF-beta homolog.Science. 1996; 274: 1389-1391Crossref PubMed Scopus (413) Google Scholar, 26Kimura K.D. Tissenbaum H.A. Liu Y. Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.Science. 1997; 277: 942-946Crossref PubMed Scopus (1715) Google Scholar]. To determine if the known downstream effectors of DAF-7/TGF-β and DAF-2/Insulin signaling that mediate dauer formation are also required for mediating the L2d rewiring caused by daf-7(lf) or daf-2(lf) [27Patterson G.I. Koweek A. Wong A. Liu Y. Ruvkun G. The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway.Genes Dev. 1997; 11: 2679-2690Crossref PubMed Scopus (161) Google Scholar, 28Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans.Nature. 1997; 389: 994-999Crossref PubMed Scopus (1536) Google Scholar], we generated compound mutants carrying daf-12(rh61) in combination with mutations that impair these effectors of the TGF-β or insulin signaling pathways and determined the number of seam cells in young adults. We found that the downstream effector of the TGF-β signaling pathway, daf-3, and the downstream effector of the insulin signaling pathway, daf-16, were required for the suppression mediated by the daf-7(lf) mutation and the daf-2(lf) mutation, respectively (Figures 3C and 3D). These results are consistent with the finding that daf-3 was also required for the ascaroside-mediated suppression of daf-12(rh61) (Figure 3B). To determine whether the TGF-β and insulin signaling pathways act in parallel to modulate temporal cell fates, we tested for crosstalk between these pathways in the context of suppression of daf-12(rh61) phenotypes. Spe" @default.
• W2945202325 created "2019-05-29" @default.
• W2945202325 creator A5067882558 @default.
• W2945202325 creator A5069643936 @default.
• W2945202325 date "2019-06-01" @default.
• W2945202325 modified "2023-10-16" @default.
• W2945202325 title "Pheromones and Nutritional Signals Regulate the Developmental Reliance on let-7 Family MicroRNAs in C. elegans" @default.
• W2945202325 cites W1631908837 @default.
• W2945202325 cites W1973699456 @default.
• W2945202325 cites W1976416661 @default.
• W2945202325 cites W1977816123 @default.
• W2945202325 cites W1986006829 @default.
• W2945202325 cites W1989702673 @default.
• W2945202325 cites W1993519767 @default.
• W2945202325 cites W1999989614 @default.
• W2945202325 cites W2005676064 @default.
• W2945202325 cites W2017352536 @default.
• W2945202325 cites W2024000520 @default.
• W2945202325 cites W2027256623 @default.
• W2945202325 cites W2036157241 @default.
• W2945202325 cites W2042165715 @default.
• W2945202325 cites W2044400161 @default.
• W2945202325 cites W2044568253 @default.
• W2945202325 cites W2052722944 @default.
• W2945202325 cites W2057039167 @default.
• W2945202325 cites W2062376760 @default.
• W2945202325 cites W2066919447 @default.
• W2945202325 cites W2068427957 @default.
• W2945202325 cites W2088019468 @default.
• W2945202325 cites W2097344907 @default.
• W2945202325 cites W2103246958 @default.
• W2945202325 cites W2104981180 @default.
• W2945202325 cites W2110819817 @default.
• W2945202325 cites W2120141187 @default.
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• W2945202325 cites W2593451051 @default.
• W2945202325 cites W2606359550 @default.
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