Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 303 (5658): 663-666

Copyright © 2004 by the American Association for the Advancement of Science

Crosstalk Between the EGFR and LIN-12/Notch Pathways in C. elegans Vulval Development

Andrew S. Yoo,1* Carlos Bais,2* Iva Greenwald2{dagger}

Abstract: The Caenorhabditis elegans vulva is an important paradigm for cell-cell interactions in animal development. The fates of six vulval precursor cells are patterned through the action of the epidermal growth factor receptor–mitogen-activated protein kinase (EGFR-MAPK) inductive signaling pathway, which specifies the 1° fate, and the LIN-12/Notch lateral signaling pathway, which specifies the 2° fate. Here, we provide evidence that the inductive signal is spatially graded and initially activates the EGFR-MAPK pathway in the prospective 2° cells. Subsequently, this effect is counteracted by the expression of multiple new negative regulators of the EGFR-MAPK pathway, under direct transcriptional control of the LIN-12–mediated lateral signal.

1 Integrated Program in Cellular, Molecular, and Biophysical Studies, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA.
2 Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, Room 720, New York, NY 10032, USA.

Back to Top

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: greenwald{at}

Discovery of two GLP-1/Notch target genes that account for the role of GLP-1/Notch signaling in stem cell maintenance.
A. M. Kershner, H. Shin, T. J. Hansen, and J. Kimble (2014)
PNAS 111, 3739-3744
   Abstract »    Full Text »    PDF »
Opposing Feedbacks on Ras Tune Receptor Tyrosine Kinase Signaling.
M. Perry and C. Desplan (2013)
Science Signaling 6, pe35
   Abstract »    Full Text »    PDF »
Kinetics of gene derepression by ERK signaling.
B. Lim, N. Samper, H. Lu, C. Rushlow, G. Jimenez, and S. Y. Shvartsman (2013)
PNAS 110, 10330-10335
   Abstract »    Full Text »    PDF »
SEL-10/Fbw7-dependent negative feedback regulation of LIN-45/Braf signaling in C. elegans via a conserved phosphodegron.
C. de la Cova and I. Greenwald (2012)
Genes & Dev. 26, 2524-2535
   Abstract »    Full Text »    PDF »
Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.
C.-W. Franzke, C. Cobzaru, A. Triantafyllopoulou, S. Loffek, K. Horiuchi, D. W. Threadgill, T. Kurz, N. van Rooijen, L. Bruckner-Tuderman, and C. P. Blobel (2012)
J. Exp. Med. 209, 1105-1119
   Abstract »    Full Text »    PDF »
Geometry, epistasis, and developmental patterning.
F. Corson and E. D. Siggia (2012)
PNAS 109, 5568-5575
   Abstract »    Full Text »    PDF »
Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal-Regulated Kinase Signaling.
A. A. Friedman, G. Tucker, R. Singh, D. Yan, A. Vinayagam, Y. Hu, R. Binari, P. Hong, X. Sun, M. Porto, et al. (2011)
Science Signaling 4, rs10
   Abstract »    Full Text »    PDF »
Spatial Regulation of lag-2 Transcription During Vulval Precursor Cell Fate Patterning in Caenorhabditis eleganslag-2.
X. Zhang and I. Greenwald (2011)
Genetics 188, 847-858
   Abstract »    Full Text »    PDF »
A growing molecular toolbox for the functional analysis of microRNAs in Caenorhabditis elegans.
J. Jo and A. Esquela-Kerscher (2011)
Briefings in Functional Genomics 10, 175-180
   Abstract »    Full Text »    PDF »
Constitutive activated Cdc42-associated kinase (Ack) phosphorylation at arrested endocytic clathrin-coated pits of cells that lack dynamin.
H. Shen, S. M. Ferguson, N. Dephoure, R. Park, Y. Yang, L. Volpicelli-Daley, S. Gygi, J. Schlessinger, and P. De Camilli (2011)
Mol. Biol. Cell 22, 493-502
   Abstract »    Full Text »    PDF »
Executing multicellular differentiation: quantitative predictive modelling of C.elegans vulval development.
N. Bonzanni, E. Krepska, K. A. Feenstra, W. Fokkink, T. Kielmann, H. Bal, and J. Heringa (2009)
Bioinformatics 25, 2049-2056
   Abstract »    Full Text »    PDF »
Direct Response to Notch Activation: Signaling Crosstalk and Incoherent Logic.
A. Krejci, F. Bernard, B. E. Housden, S. Collins, and S. J. Bray (2009)
Science Signaling 2, ra1
   Abstract »    Full Text »    PDF »
Intraspecific evolution of the intercellular signaling network underlying a robust developmental system.
J. Milloz, F. Duveau, I. Nuez, and M.-A. Felix (2008)
Genes & Dev. 22, 3064-3075
   Abstract »    Full Text »    PDF »
The Activated Notch1 Receptor Cooperates with {alpha}-Enolase and MBP-1 in Modulating c-myc Activity.
K.-W. Hsu, R.-H. Hsieh, Y.-H. W. Lee, C.-H. Chao, K.-J. Wu, M.-J. Tseng, and T.-S. Yeh (2008)
Mol. Cell. Biol. 28, 4829-4842
   Abstract »    Full Text »    PDF »
A Novel Sorting Nexin Modulates Endocytic Trafficking and {alpha}-Secretase Cleavage of the Amyloid Precursor Protein.
S. Schobel, S. Neumann, M. Hertweck, B. Dislich, P.-H. Kuhn, E. Kremmer, B. Seed, R. Baumeister, C. Haass, and S. F. Lichtenthaler (2008)
J. Biol. Chem. 283, 14257-14268
   Abstract »    Full Text »    PDF »
Regulation of Lymphocyte Development by Cell-Type-Specific Interpretation of Notch Signals.
L. Nie, S. S. Perry, Y. Zhao, J. Huang, P. W. Kincade, M. A. Farrar, and X.-H. Sun (2008)
Mol. Cell. Biol. 28, 2078-2090
   Abstract »    Full Text »    PDF »
Wnt signal from multiple tissues and lin-3/EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans.
T. R. Myers and I. Greenwald (2007)
PNAS 104, 20368-20373
   Abstract »    Full Text »    PDF »
Notch-GATA synergy promotes endoderm-specific expression of ref-1 in C. elegans.
A. Neves, K. English, and J. R. Priess (2007)
Development 134, 4459-4468
   Abstract »    Full Text »    PDF »
The C. elegans ROR receptor tyrosine kinase, CAM-1, non-autonomously inhibits the Wnt pathway.
J. L. Green, T. Inoue, and P. W. Sternberg (2007)
Development 134, 4053-4062
   Abstract »    Full Text »    PDF »
Co-regulation by Notch and Fos is required for cell fate specification of intermediate precursors during C. elegans uterine development.
K. S. Oommen and A. P. Newman (2007)
Development 134, 3999-4009
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of {gamma}-Secretase.
T. Li, H. Wen, C. Brayton, P. Das, L. A. Smithson, A. Fauq, X. Fan, B. J. Crain, D. L. Price, T. E. Golde, et al. (2007)
J. Biol. Chem. 282, 32264-32273
   Abstract »    Full Text »    PDF »
{gamma}-Secretase Inhibitor Prevents Notch3 Activation and Reduces Proliferation in Human Lung Cancers.
J. Konishi, K. S. Kawaguchi, H. Vo, N. Haruki, A. Gonzalez, D. P. Carbone, and T. P. Dang (2007)
Cancer Res. 67, 8051-8057
   Abstract »    Full Text »    PDF »
The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1.
W.-R. Liao, R.-H. Hsieh, K.-W. Hsu, M.-Z. Wu, M.-J. Tseng, R.-T. Mai, Y.-H. Wu Lee, and T.-S. Yeh (2007)
Carcinogenesis 28, 1867-1876
   Abstract »    Full Text »    PDF »
Computational modeling of Caenorhabditis elegans vulval induction.
X. Sun and P. Hong (2007)
Bioinformatics 23, i499-i507
   Abstract »    Full Text »    PDF »
Combinatorial signaling in the specification of primary pigment cells in the Drosophila eye.
R. Nagaraj and U. Banerjee (2007)
Development 134, 825-831
   Abstract »    Full Text »    PDF »
SEL-2, the C. elegans neurobeachin/LRBA homolog, is a negative regulator of lin-12/Notch activity and affects endosomal traffic in polarized epithelial cells.
N. de Souza, L. G. Vallier, H. Fares, and I. Greenwald (2007)
Development 134, 691-702
   Abstract »    Full Text »    PDF »
Distinct roles of the Pumilio and FBF translational repressors during C. elegans vulval development.
C. B. Walser, G. Battu, E. F. Hoier, and A. Hajnal (2006)
Development 133, 3461-3471
   Abstract »    Full Text »    PDF »
Cell fate-specific regulation of EGF receptor trafficking during Caenorhabditis elegans vulval development.
A. Stetak, E. F. Hoier, A. Croce, G. Cassata, P. P. Di Fiore, and A. Hajnal (2006)
EMBO J. 25, 2347-2357
   Abstract »    Full Text »    PDF »
Intercellular coupling amplifies fate segregation during Caenorhabditis elegans vulval development.
C. A. Giurumescu, P. W. Sternberg, and A. R. Asthagiri (2006)
PNAS 103, 1331-1336
   Abstract »    Full Text »    PDF »
DEVELOPMENTAL BIOLOGY: Enhanced: Encountering MicroRNAs in Cell Fate Signaling.
X. Karp and V. Ambros (2005)
Science 310, 1288-1289
   Abstract »    Full Text »    PDF »
LIN-12/Notch Activation Leads to MicroRNA-Mediated Down-Regulation of Vav in C. elegans.
A. S. Yoo and I. Greenwald (2005)
Science 310, 1330-1333
   Abstract »    Full Text »    PDF »
LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans.
D. D. Shaye and I. Greenwald (2005)
Development 132, 5081-5092
   Abstract »    Full Text »    PDF »
Regulating the dynamics of EGF receptor signaling in space and time.
B.-Z. Shilo (2005)
Development 132, 4017-4027
   Abstract »    Full Text »    PDF »
The love-hate relationship between Ras and Notch.
M. V. Sundaram (2005)
Genes & Dev. 19, 1825-1839
   Abstract »    Full Text »    PDF »
Chromatin regulation and sumoylation in the inhibition of Ras-induced vulval development in Caenorhabditis elegans.
G. Poulin, Y. Dong, A. G. Fraser, N. A. Hopper, and J. Ahringer (2005)
EMBO J. 24, 2613-2623
   Abstract »    Full Text »    PDF »
The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions.
T. A. Berset, E. F. Hoier, and A. Hajnal (2005)
Genes & Dev. 19, 1328-1340
   Abstract »    Full Text »    PDF »
Dominant-Negative Notch3 Receptor Inhibits Mitogen-Activated Protein Kinase Pathway and the Growth of Human Lung Cancers.
N. Haruki, K. S. Kawaguchi, S. Eichenberger, P. P. Massion, S. Olson, A. Gonzalez, D. P. Carbone, and T. P. Dang (2005)
Cancer Res. 65, 3555-3561
   Abstract »    Full Text »    PDF »
Computational insights into Caenorhabditis elegans vulval development.
J. Fisher, N. Piterman, E. J. A. Hubbard, M. J. Stern, and D. Harel (2005)
PNAS 102, 1951-1956
   Abstract »    Full Text »    PDF »
The bHLH genes GL3 and EGL3 participate in an intercellular regulatory circuit that controls cell patterning in the Arabidopsis root epidermis.
C. Bernhardt, M. Zhao, A. Gonzalez, A. Lloyd, and J. Schiefelbein (2005)
Development 132, 291-298
   Abstract »    Full Text »    PDF »
Nuclear {beta}II-Tubulin Associates with the Activated Notch Receptor to Modulate Notch Signaling.
T.-S. Yeh, R.-H. Hsieh, S.-C. Shen, S.-H. Wang, M.-J. Tseng, C.-M. Shih, and J.-J. Lin (2004)
Cancer Res. 64, 8334-8340
   Abstract »    Full Text »    PDF »
DEVELOPMENTAL BIOLOGY: A Pattern of Precision.
P. W. Sternberg (2004)
Science 303, 637-638
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882