The P-type ATPase CATP-1 is novel regulator of C. elegans developmental timing that acts independently of its predicted pump function

Abstract

During postembryonic stages, metazoans synchronize the development of a large number of cells, tissues and organs by mechanisms that remain largely unknown. In Caenorhabditis elegans larvae, an invariant cell lineage is tightly coordinated with four successive molts, thus defining a genetically tractable system to analyze the mechanisms underlying developmental synchronization. Illegitimate activation of nicotinic acetylcholine receptors (nAChRs) by the nicotinic agonist dimethylphenylpiperazinium (DMPP) during the second larval stage (L2) of C. elegans causes a lethal heterochronic phenotype. DMPP exposure delays cell division and differentiation without affecting the molt cycle, hence resulting in deadly exposure of a defective cuticle to the surrounding environment. In a screen for DMPP-resistant mutants, we identified catp-1 as a gene coding for a predicted cation-transporting P-type ATPase expressed in the epidermis. Larval development was specifically slowed down at the L2 stage in catp-1 mutants compared with wild-type animals and was not further delayed after exposure to DMPP. We demonstrate that CATP-1 interacts with the insulin/IGF and Ras-MAPK pathways to control several postembryonic developmental events. Interestingly, these developmental functions can be fulfilled independently of the predicted cation-transporter activity of CATP-1, as pump-dead engineered variants of CATP-1 can rescue most catp-1-mutant defects. These results obtained in vivo provide further evidence for the recently proposed pump-independent scaffolding functions of P-type ATPases in the modulation of intracellular signaling.