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Vol. 16, Issue 1, 106-116, January 2005
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* Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands;
Hubrecht Laboratory/Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands;
|| Institute of Parasitology, Academy of Sciences of the Czech Republic, Ceske Budejovice 370 05, Czech Republic; and
# Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
Submitted June 16, 2004;
Revised October 15, 2004;
Accepted October 19, 2004
Monitoring Editor: Jean Schwarzbauer
The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts. Deletion of the catalytic domain from pxf-1 leads to hypodermal defects, resulting in lethality. The cuticle secreted by pxf-1 mutants is disorganized and can often not be shed during molting. At later stages, hypodermal degeneration is seen and animals that reach adulthood frequently die with a burst vulva phenotype. Importantly, disruption of rap-1 leads to a similar, but less severe phenotype, which is enhanced by the simultaneous removal of rap-2. In addition, the lethal phenotype of pxf-1 can be rescued by expression of an activated version of rap-1. Together these results demonstrate that the pxf-1/rap pathway in C. elegans is required for maintenance of epithelial integrity, in which it probably functions in polarized secretion.
These authors contributed equally to this work.
Present address: Department of Molecular and Cellular Neurobiology, Vrije Universiteit, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands.
¶ Present address: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
@ Present address: Institute for Cell Biology and Genetics, Erasmus University Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands.
** Corresponding author. E-mail address: G.J.T.Zwartkruis{at}med.uu.nl.
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