Intimate functional interactions between TGS1 and the Smn complex revealed by an analysis of the Drosophila eye development
| Autor: | Maurizio Gatti, Elisabetta Bucciarelli, Paolo Maccallini, James G. Wakefield, Stefano Cacchione, Laura Ciapponi, Veronica Lisi, S. D'Angeli, Francesca Bavasso, Livia Scatolini, Gemma Noviello, Giovanni Cenci, Grazia D. Raffa, Valeria Palumbo |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Life Cycles
Cancer Research Organogenesis animal diseases Trimethylguanosine synthase QH426-470 Eye Biochemistry RNA interference Larvae 0302 clinical medicine SMN complex Medicine and Health Sciences Morphogenesis Drosophila Proteins Genetics (clinical) 0303 health sciences Small nuclear RNA biology Drosophila Melanogaster Sense Organ Development Eukaryota Gene Expression Regulation Developmental RNA-Binding Proteins SMN Complex Proteins Animal Models Organ Size Phenotype Cell biology Insects Nucleic acids Phenotypes Eye Development Experimental Organism Systems Genetic interference Imaginal Discs Gene Knockdown Techniques Epigenetics Drosophila Anatomy Drosophila melanogaster Research Article Arthropoda TGS1 Transgene Down-Regulation Research and Analysis Methods Drosophila TGS1 03 medical and health sciences Model Organisms Ocular System Genetics medicine Animals Non-coding RNA Molecular Biology Ecology Evolution Behavior and Systematics 030304 developmental biology Organisms Biology and Life Sciences Spinal muscular atrophy medicine.disease biology.organism_classification Invertebrates nervous system diseases nervous system Animal Studies Eye development Eyes RNA Genes Lethal Gene expression Head Organism Development 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 16, Iss 5, p e1008815 (2020) |
| Popis: | 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). 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 understand the molecular mechanisms underlying SMA pathogenesis and devise new therapies for this genetic disease. Author summary We explored the functional relationships between TGS1 and SMN using Drosophila as model organism. TGS1 is an enzyme that modifies the structure of the 5’-end of several RNAs, including telomerase RNA and the small nuclear RNAs (snRNAs) that are required for messenger RNA maturation. The SMN protein regulates snRNAs biogenesis and mutations in human SMN cause Spinal Muscular Atrophy (SMA), a devastating disorder characterized by neurodegeneration, progressive paralysis and death. We show that mutations in the Drosophila TGS1 (dTgs1) gene cause lethality, which is rescued by a human TGS1 transgene. We also show that the dTgs1 protein physically interacts with all subunits of the Smn complex, and that downregulation of either dTgs1 or Smn leads to a reduced Drosophila eye size. Notably, overexpression of dTgs1 partially rescues the eye defects caused by Smn knockdown, and vice versa, indicating that these genes cooperate in eye development. These results suggest that the eye model can be exploited for screens aimed at detection of chemical and genetic modifiers of the eye mutant phenotype elicited by dTgs1 and Smn deficiency, providing new clues about SMA pathogenesis and potential therapies. |
| Databáze: | OpenAIRE |
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