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

Lanfranco, Maia; Cacciottolo, Rebecca; Borg, Rebecca; Vassallo, Neville; Juge, François; Bordonne, Rémy; Cauchi, Ruben J.

doi:10.1002/1873-3468.12853

Cited by 19 publications

(50 citation statements)

References 46 publications

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“…1B), we first carried out in silico bioinformatic analyses. As mentioned above, there have been conflicting reports regarding the conservation (or lack thereof) of certain Gemin proteins in Drosophila (KROISS et al 2008;LANFRANCO et al 2017). In particular, Gem4, Gem6, Gem7 and Gem8 were originally thought to have been lost from Dipteran genomes, although clear orthologues of Gem6-7-8 can been readily identifed in Hymenoptera, and other insects (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…search https://www.ncbi.nlm.nih.gov/protein). Lanfranco et al (2017) recently suggested that Hezron/CG14164 encodes the Drosophila orthologue of Gem6. Our bioinformatic analysis suggested that CG14164 is actually more closely related to human Lsm12, an Sm-like protein that contains a C-terminal methyltransferase domain (ALBRECHT AND LENGAUER 2004).…”

Section: Resultsmentioning

confidence: 99%

“…A recent study presented evidence suggesting the "full conservation" of the SMN complex in fruit flies (LANFRANCO et al 2017), and arguing that Gem4 and Gem6-7-8 are present in Diptera. In this report, we re-investigate this issue, showing that among the four novel factors identified by Lanfranco et al (2017), only Gaulos (CG2941) is orthologous to a metazoan SMN complex protein (Gem4). Using comparative genomic analysis, we conclusively demonstrate that Hezron (CG14164), Sabbat (CG31950) and…”

Section: Introductionmentioning

confidence: 99%

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

Matera

Raimer

Schmidt

et al. 2018

Preprint

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Spinal Muscular Atrophy (SMA) is caused by homozygous mutations in the human survival motor neuron 1 (SMN1) gene. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. SMN is part of an oligomeric complex with core binding partners, collectively called Gemins. Biochemical and cell biological studies demonstrate that certain Gemins are required for proper snRNP assembly and transport. However, the precise functions of most Gemins are unknown. To gain a deeper understanding of the SMN complex in the context of metazoan evolution, we investigated the composition of the SMN complex in Drosophila melanogaster. Using a stable transgenic line that exclusively expresses Flag-tagged SMN from its native promoter, we previously found that Gemin2, Gemin3, Gemin5, and all nine classical Sm proteins, including Lsm10 and Lsm11, co-purify with SMN. Here, we show that CG2941 is also highly enriched in the pulldown. Reciprocal co-immunoprecipitation reveals that epitope-tagged CG2941 interacts with endogenous SMN in Schneider2 cells. Bioinformatic comparisons show that CG2941 shares sequence and structural similarity with metazoan Gemin4.Additional analysis shows that three other genes (CG14164, CG31950 and CG2371) are not orthologous to Gemins 6-7-8, respectively, as previously suggested. In D.melanogaster, CG2941 is located within an evolutionarily recent genomic triplication with two other nearly identical paralogous genes (CG32783 and CG32786). RNAimediated knockdown of CG2941 and its two close paralogs reveals that Gemin4 is essential for organismal viability.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Matera

Raimer

Schmidt

et al. 2018

Preprint

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“…Interestingly, the fly SMN complex contains only four bona fide Gemin proteins (Gem2, Gem3, Gem4/Glos and Gem5/Rig) [49,50,74]. The existence of potential homologs of Gem6, 7 and 8 was postulated by [50] but was not confirmed in a subsequent study [49]. Our AP/MS analyses of embryo extracts showed that Smn strongly co-precipitates with GFP-dTgs1.…”

Section: Discussionmentioning

confidence: 76%

“…shown that that dTgs1 interacts with the Gemin3 subunit of the SMN complex in a twohybrid assay [37]. Interestingly, the fly SMN complex contains only four bona fide Gemin proteins (Gem2, Gem3, Gem4/Glos and Gem5/Rig) [49,50,74]. The existence of potential homologs of Gem6, 7 and 8 was postulated by [50] but was not confirmed in a subsequent study [49].…”

Section: Discussionmentioning

confidence: 98%

Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development

Maccallini

Bavasso

Scatolini

et al. 2020

Preprint

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Trimethylguanosine synthase 1 (TGS1) is a conserved enzyme that mediates formation of the trimethylguanosine cap on several RNAs, including snRNAs and telomerase RNA. Previous studies have shown that TGS1 binds the Survival Motor Neuron (SMN) protein, whose deficiency causes spinal muscular atrophy (SMA). In addition, TGS1 depletion results in increased hTR levels and telomere elongation in human cells. Here, we analyzed the roles of the Drosophila orthologs of the human TGS1 and SMN genes.We show that the Drosophila TGS1 protein (dTgs1) physically interacts with all subunits of the Drosophila Smn complex (Smn, Gem2, Gem3, Gem4 and Gem5), and that a human TGS1 transgene rescues the mutant phenotype caused by dTgs1 loss. We demonstrate that both dTgs1 and Smn are required for viability of retinal progenitor cells and that downregulation of these genes leads to a reduced eye size. Importantly, overexpression of dTgs1 partially rescues the eye defects caused by Smn depletion, and vice versa. These results suggest that the Drosophila eye model can be exploited for screens aimed at the identification of genes and drugs that modify the phenotypes elicited by Tgs1 and Smn deficiency. These modifiers could help to devise new therapies for SMA and diseases caused by telomerase insufficiency.

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Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome

Altassan

Qudair

Alokaili

et al. 2022

American J of Med Genetics Pt A

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Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients.Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.

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

Cited by 19 publications

References 46 publications

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

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

Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development

Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome

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