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feh-1 and apl-1, the Caenorhabditis elegans orthologues of mammalian Fe65 and ß-amyloid precursor protein genes, are involved in the same pathway that controls nematode pharyngeal pumping

¹ Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via S. Pansini, 5, I-80131, Napoli, Italy
² International Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, Via G. Marconi, 10, I-80125, Napoli, Italy

Author for correspondence: (e-mail: zambrano{at}unina.it )

Accepted 3 January 2002

The multigenic family of mammalian Fe65s encodes three highly similar proteins with the same modular organisation: a WW domain and two phosphotyrosine-binding domains. The PTB2 domain of these proteins binds to the cytosolic domains of the Alzheimer's ß-amyloid precursor protein APP and related proteins APLP1 and APLP2, generating a highly redundant system that is hard to dissect by reverse genetics. By searching potential Fe65-like genes in the nematode Caenorhabditis elegans, we identified a single gene, feh-1 (Fe65 homolog-1), encoding a protein with a high sequence similarity to mammalian Fe65s. FEH-1 is also functionally related to mammalian orthologues; in fact its PTB2 domain binds to APL-1, the product of the C. elegans orthologue of APP. Staining with specific antibodies show that the neuromuscular structures of the pharynx are the sites in which FEH-1 is present at highest levels. Expression studies with reporters indicate that the feh-1 gene is also expressed by a subset of the worm neurons.

We generated and isolated a deletion allele of feh-1, and the corresponding homozygous mutants arrest as late embryos or as L1 larvae, demonstrating for the first time an essential role for a Fe65-like gene in vivo. The pharynx of homozygous larvae does not contract and the worms cannot feed. Analysis of pharyngeal pumping in heterozygous worms and in feh-1 RNA-interfered worms indicates that dosage of feh-1 function affects the rate of pharyngeal contraction in C. elegans. Interference with apl-1 double-stranded RNA showed a similar effect on pharyngeal pumping, suggesting that FEH-1 and APL-1 are involved in the same pathway. The non-redundant system of the nematode will prove useful for studying the basic biology of the Fe65-APP interaction and the molecular events regulated by this evolutionarily conserved system of interacting proteins.

Key words: Protein-protein interaction, Alzheimer's disease, RNAi

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