title: Two neuronal, nuclear-localized RNA binding proteins involved in synaptic transmission.
abstract: While there is evidence that distinct protein isoforms resulting from alternative pre-mRNA splicing play critical roles in neuronal development and function, little is known about molecules regulating alternative splicing in the nervous system. Using Caenorhabditis elegans as a model for studying neuron/target communication, we report that unc-75 mutant animals display neuroanatomical and behavioral defects indicative of a role in modulating GABAergic and cholinergic neurotransmission but not neuronal development. We show that unc-75 encodes an RRM domain-containing RNA binding protein that is exclusively expressed in the nervous system and neurosecretory gland cells. UNC-75 protein, as well as a subset of related C. elegans RRM proteins, localizes to dynamic nuclear speckles; this localization pattern supports a role for the protein in pre-mRNA splicing. We found that human orthologs of UNC-75, whose splicing activity has recently been documented in vitro, are expressed nearly exclusively in brain and when expressed in C. elegans, rescue unc-75 mutant phenotypes and localize to subnuclear puncta. Furthermore, we report that the subnuclear-localized EXC-7 protein, the C. elegans ortholog of the neuron-restricted Drosophila ELAV splicing factor, acts in parallel to UNC-75 to also affect cholinergic synaptic transmission. In conclusion, we identified a new neuronal, putative pre-mRNA splicing factor, UNC-75, and show that UNC-75, as well as the C. elegans homolog of ELAV, is required for the fine tuning of synaptic transmission. These findings thus provide a novel molecular link between pre-mRNA splicing and presynaptic function.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, New York, NY 10032, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.forename: Angie
authors.initials: A
authors.lastname: Duke
authors.forename: James B
authors.initials: JB
authors.lastname: Rand
authors.forename: Oliver
authors.initials: O
authors.lastname: Hobert
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology; D010802:Phylogeny; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; C473926:EXC-7 protein, C elegans; D016601:RNA-Binding Proteins