Different Levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates

Katz, Wendy S.; Hill, Russell J.; Clandinin, Thomas R.; Sternberg, Paul W.

doi:10.1016/0092-8674(95)90317-8

Cited by 189 publications

(199 citation statements)

References 42 publications

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“…6). This result is in agreement with LIN-3 dosage experiments, wherein increasing LIN-3 production by the AC permits specification of 1°and 2°fates (4).…”

supporting

confidence: 80%

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Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development

Giurumescu

Sternberg

Asthagiri

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…6). This result is in agreement with LIN-3 dosage experiments, wherein increasing LIN-3 production by the AC permits specification of 1°and 2°fates (4).…”

supporting

confidence: 80%

“…Indeed, a gradient in LIN-3 signaling has been observed indirectly in vivo by using a sensitive reporter of LIN-3-mediated transcriptional activity (2). These observations strongly support the notion that LIN-3 acts as a morphogen, a soluble factor whose spatial concentration gradient influences cell fate choices (3,4).…”

supporting

confidence: 65%

Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development

Giurumescu

Sternberg

Asthagiri

2006

Proc. Natl. Acad. Sci. U.S.A.

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“…n.s, not significant. duct fate ( Figure 4G); but they differed markedly in their ability to rescue vulval development ( Figure 4H), another LIN-3/EGF-dependent process (Hill and Sternberg 1992;Katz et al 1995). The isoforms also differed in their ability to induce pore-to-duct cell fate transformations in a WT background ( Figure 4I), and to rescue lpr-1(cs207) lethality (Figure 4J), with LIN-3XL having the weakest activity.…”

Section: Lpr-1 Localizes To Both Intracellular and Apical Extracellulmentioning

confidence: 99%

“…a Heat shock at bean stage at 31°for 1 hr, returned to 20°. b syIs6 generated by Katz et al (1995). Ras signaling is sufficient to bypass lpr-1, it does not appear to be required for lumen integrity either on its own or in parallel to lpr-1.…”

Section: Let-23/egfr Localizes To Apical Membranes During Tube Elongamentioning

confidence: 99%

The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans

Pu¹,

Stone²,

Burdick³

et al. 2017

Genetics

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Lipocalins are secreted cup-shaped glycoproteins that bind sterols, fatty acids, and other lipophilic molecules. Lipocalins have been implicated in a wide array of processes related to lipophilic cargo transport, sequestration, and signaling, and several are used as biomarkers for human disease, but the functions of most lipocalins remain poorly understood. Here we show that the Caenorhabditis elegans lipocalin LPR-1 is required to maintain apical membrane integrity and a continuous lumen in two narrow unicellular tubes, the excretory duct and pore, during a period of rapid lumen elongation. LPR-1 fusion protein is expressed by the duct and pore and accumulates both intracellularly and in apical extracellular compartments, but it can also function cell nonautonomously when provided from outside of the excretory system. lpr-1 mutant defects can be rescued by increased signaling through the epidermal growth factor (EGF)-Ras-extracellular signal regulated kinase (ERK) pathway, which promotes the more elongated duct vs. less elongated pore tube fate. Spatial and temporal rescue experiments indicate that Ras signaling acts within the duct and pore tubes during or prior to cell fate determination to bypass the requirement for LPR-1. lpr-1 mutations did not disrupt LIN-3/EGF-dependent duct-fate specification, prevent functioning of any specific LIN-3/EGF isoform, or alter LET-23/EGFR localization, and reduced signaling did not phenocopy or enhance lpr-1 mutant defects. These data suggest that LPR-1 protects lumen integrity through a LIN-3/EGFindependent mechanism, but that increased signaling upregulates some target(s) that can compensate for lpr-1 absence.

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“…MPK-1/ERK activation in P6.p modulates the activity of effector transcription factors such as the ELK1/Ets-family transcription factor LIN-1 and the FoxB transcription factor LIN-31, thereby specifying the 1°vulval fate in P6.p (Miller et al 1993;Tan et al 1998;Jacobs et al 1998). The neighboring P5.p and P7.p cells are thought to receive a weaker LIN-3/EGF signal from the anchor cell (Katz et al 1995) as well as a lateral Notch signal emitted from the 1°cell P6.p, inducing them to adopt a 2°v ulval fate (Chen and Greenwald 2004 (Figure 1). For example, transcription factors such as LIN-1/Ets and LIN-31/ Forkhead are required to repress 1°cell fate specification in VPCs other than P6.p (Miller et al 1993;Beitel et al 1995).…”

mentioning

confidence: 99%

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

et al. 2015

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Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinasedependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals.KEYWORDS Mediator complex; CDK8; MED23; MED15; EGFR; Notch P RECISE regulation of transcription is required to execute developmental programs such as proliferation and cell fate determination. The Mediator complex ("Mediator") is a conserved eukaryotic transcriptional coregulator of RNA polymerase II (Pol II) transcription (Malik and Roeder 2010;Poss et al. 2013). Mediator consists of 30 subunits that assemble into four modules. "Core" Mediator consists of three of the four modules: the head and middle modules, which contact Pol II, and the tail module, which serves as a docking site for transcription factors. The fourth module, the dissociable cyclin dependent kinase 8 (CDK8) kinase module (CKM), interacts with transcription factors, core Mediator, chromatin, and the Pol II machinery to either repress or activate transcription (Malik and Roeder 2010;Nemet et al. 2014 transcription, tail and CKM subunits regulate specific transcriptional programs in animal development or physiology (Malik and Roeder 2010;Nemet et al. 2014). The CKM consists of enzymatic subunits CDK8 and cyclin C, and structural subunits MED12 and MED13 that tether the CKM to core Mediator (Tsai et al. 2013). C...

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Different Levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates

Cited by 189 publications

References 42 publications

Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development

Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development

The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

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