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.

Novel interactors of the Drosophila Survival Motor Neuron (SMN) Complex suggest its full conservation

“…The SMN complex is central to cellular metabolism as demonstrated by its presence in nearly all eukaryotes [6]. In contrast to the expanded version in metazoans including humans, Drosophila was reported to have a minimal SMN complex composed of only SMN, Gem-in2/3/5, and, possibly, Unrip [11,[14][15][16]. Hence, it has been suggested that the human SMN complex gained complexity in evolution through the incorporation of the remaining Gemins [11].…”

“…Making use of this model, we and others have previously shown that loss of SMN, Gemin2, Gemin3, Gemin5, and Unrip leads to neuromuscular dysfunction . Importantly, components of the Drosophila SMN complex were shown to interact genetically in addition to physically . Attempting at furthering our understanding of the mechanics of the Drosophila SMN complex, here we report on the identification and initial characterisation of novel interacting partners.…”

“…Hence, in contrast to the elaborate ninemembered version in vertebrates, including humans, in its simplest form found in the fission yeast Schizosaccharomyces pombe and the parasitic protozoan Trypanosoma brucei, the SMN complex is composed of only SMN and Gemin2 [11][12][13]. A slightly larger SMN complex comprising SMN, Gemin2, Gemin3, Gemin5, and, possibly, Unrip amongst its constituents is present in the fruit fly Drosophila melanogaster [14][15][16]. Interestingly, orthologues of most of the remaining Gemins appear to be absent in Drosophila although they are present in closely related species including the honey bee Apis mellifera and the parasitic wasp Nasonia vitripennis [11].…”

Composition of the Survival Motor Neuron (SMN) complex in Drosophila melanogaster

“…construct lacking its N-terminal helicase domain, called Gem3 BART(BORG et al 2015), were used in combination with a deficiency allele Df(1)ED6716 (RYDER et al 2007) that spans the 3F2-4B3 interval on the X chromosome that includes CG2941/Gaulos(LANFRANCO et al 2017). Loss of one copy of this region in combination with panmuscular expression of Gem3 BART led to a marked age-dependent enhancement of the phenotype(LANFRANCO et al 2017).…”

A subset of SMN complex members have a specific role in tissue regeneration via ERBB pathway-mediated proliferation

“…Genetic interactions have been observed among SMN complex genes [23][24][25] . To study whether there is a synergy among the three genes involved in regeneration, we generated an smn1 and gemin5 double mutant and studied the effect of simultaneous depletion of two genes on morphology and hair cell regeneration.…”