title: Novel isoforms of Dlg are fundamental for neuronal development in Drosophila.
abstract: Drosophila discs-large (dlg) mutants exhibit multiple developmental abnormalities, including severe defects in neuronal differentiation and synaptic structure and function. These defects have been ascribed to the loss of a single gene product, Dlg-A, a scaffold protein thought to be expressed in many cell types. Here, we describe that additional isoforms arise as a consequence of different transcription start points and alternative splicing of dlg. At least five different dlg gene products are predicted. We identified a subset of dlg-derived cDNAs that include novel exons encoding a peptide homologous to the N terminus of the mammalian protein SAP97/hDLG (S97N). Dlg isoforms containing the S97N domain are expressed at larval neuromuscular junctions and within the CNS of both embryos and larvae but are not detectable in epithelial tissues. Strong hypomorphic dlg alleles exhibit decreased expression of S97N, which may account for neural-specific aspects of the pleiomorphic dlg mutant phenotype. Selective inhibition of the expression of S97N-containing proteins in embryos by double-strand RNA leads to severe defects in neuronal differentiation and axon guidance, without overt perturbations in epithelia. These results indicate that the differential expression of dlg products correlates with distinct functions in non-neural and neural cells. During embryonic development, proteins that include the S97N domain are essential for proper neuronal differentiation and organization, acting through mechanisms that may include the adequate localization of cell fate determinants.
authors.affiliation: Programa de Fisiologia y Biofisica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile 6530499.
authors.forename: Carolina
authors.initials: C
authors.lastname: Mendoza
authors.forename: Patricio
authors.initials: P
authors.lastname: Olguín
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lafferte
authors.forename: Ulrich
authors.initials: U
authors.lastname: Thomas
authors.forename: Susanne
authors.initials: S
authors.lastname: Ebitsch
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Manuel
authors.initials: M
authors.lastname: Kukuljan
authors.forename: Jimena
authors.initials: J
authors.lastname: Sierralta
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002490:Central Nervous System / Q000196:embryology / Q000254:growth & development / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004330:Drosophila; D029721:Drosophila Proteins; D004625:Embryo, Nonmammalian / Q000294:innervation; D005091:Exons / Q000502:physiology; D020224:Expressed Sequence Tags; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007150:Immunohistochemistry; D019476:Insect Proteins / Q000235:genetics / Q000502:physiology*; D007814:Larva; D009419:Nerve Tissue Proteins / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019581:Neuropil / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012330:RNA, Double-Stranded / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D018076:DNA, Complementary; D029721:Drosophila Proteins; D019476:Insect Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012330:RNA, Double-Stranded; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila