title: feh-1 and apl-1, the Caenorhabditis elegans orthologues of mammalian Fe65 and beta-amyloid precursor protein genes, are involved in the same pathway that controls nematode pharyngeal pumping.
abstract: 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 beta-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.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via S. Pansini, 5, I-80131, Napoli, Italy. zambrano@unina.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.forename: Marida
authors.initials: M
authors.lastname: Bimonte
authors.forename: Salvatore
authors.initials: S
authors.lastname: Arbucci
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Paolo
authors.initials: P
authors.lastname: Bazzicalupo
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008322:Mammals / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D010609:Pharyngeal Muscles / Q000502:physiology*; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: C084891:APL-1 protein, C elegans; D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C467198:FEH-1 protein, C elegans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins