title: Genetic Interactions between the Members of the SMN-Gemins Complex in Drosophila.
abstract: The SMN-Gemins complex is composed of Gemins 2-8, Unrip and the survival motor neuron (SMN) protein. Limiting levels of SMN result in the neuromuscular disorder, spinal muscular atrophy (SMA), which is presently untreatable. The most-documented function of the SMN-Gemins complex concerns the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Despite multiple genetic studies, the Gemin proteins have not been identified as prominent modifiers of SMN-associated mutant phenotypes. In the present report, we make use of the Drosophila model organism to investigate whether viability and motor phenotypes associated with a hypomorphic Gemin3 mutant are enhanced by changes in the levels of SMN, Gemin2 and Gemin5 brought about by various genetic manipulations. We show a modifier effect by all three members of the minimalistic fly SMN-Gemins complex within the muscle compartment of the motor unit. Interestingly, muscle-specific overexpression of Gemin2 was by itself sufficient to depress normal motor function and its enhanced upregulation in all tissues leads to a decline in fly viability. The toxicity associated with increased Gemin2 levels is conserved in the yeast S. pombe in which we find that the cytoplasmic retention of Sm proteins, likely reflecting a block in the snRNP assembly pathway, is a contributing factor. We propose that a disruption in the normal stoichiometry of the SMN-Gemins complex depresses its function with consequences that are detrimental to the motor system.
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta GC; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Université Montpellier 1 and 2, Montpellier, France.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Borg
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Université Montpellier 1 and 2, Montpellier, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bordonne
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta GC.
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.affiliation: Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta GC.
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Cauchi
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000235:genetics; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D009046:Motor Neurons / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D055532:SMN Complex Proteins / Q000235:genetics*; D012568:Schizosaccharomyces / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; C542563:Smn protein, Drosophila