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 Caenorhabditis elegans

Genetics. 2017 Dec;207(4):1473-1488. doi: 10.1534/genetics.117.300192. Epub 2017 Sep 27.

Abstract

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.

Keywords: C. elegans; CDK-8; Cdk8; EGF receptor; Elk1; LIN-1; Med23; Notch; SUR-2; vulva.

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans Proteins / genetics*
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cyclin-Dependent Kinase 8 / genetics
  • ErbB Receptors / genetics*
  • Female
  • Genes, Reporter
  • Receptors, Notch / genetics*
  • Signal Transduction / genetics
  • Transcription Factors / genetics*
  • Transcription, Genetic
  • Vulva / growth & development
  • Vulva / metabolism
  • ets-Domain Protein Elk-1

Substances

  • Caenorhabditis elegans Proteins
  • Lin-1 protein, C elegans
  • Lin-12 protein, C elegans
  • Receptors, Notch
  • Sur-2 protein, C elegans
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • ErbB Receptors
  • Cyclin-Dependent Kinase 8