Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs

• Published in: Experimental neurology Vol. 310; pp. 1 - 13
• Main Authors: Muraoka, Yuuka, Nakamura, Aya, Tanaka, Ryo, Suda, Kojiro, Azuma, Yumiko, Kushimura, Yukie, Lo Piccolo, Luca, Yoshida, Hideki, Mizuta, Ikuko, Tokuda, Takahiko, Mizuno, Toshiki, Nakagawa, Masanori, Yamaguchi, Masamitsu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2018
• Subjects: ALS; Animals; Animals, Genetically Modified; Charcot-Marie-Tooth Disease - genetics; CMT; Disease Models, Animal; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Epistasis, Genetic - genetics; Eye - ultrastructure; FIG4; Flavoproteins - genetics; Flavoproteins - metabolism; FUS; Genetic Testing; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Long non-coding RNAs; Lysosomes - genetics; Lysosomes - ultrastructure; Microscopy, Electron, Scanning; Movement - physiology; Mutation - genetics; Neuromuscular Junction - genetics; Neuromuscular Junction - ultrastructure; Neurons - physiology; Neurons - ultrastructure; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Pupa - genetics; Retina - cytology; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; FIG4; hpRNA; Long non-coding RNAs; lncRNA; FIG 4; FUS; Drosophila; ALS; NMJ; CMT
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2018.08.009

Neuron-specific knockdown of the dFIG4 gene, a Drosophila homologue of human FIG4 and one of the causative genes for Charcot-Marie-Tooth disease (CMT), reduces the locomotive abilities of adult flies, as well as causing defects at neuromuscular junctions, such as reduced synaptic branch length in presynaptic terminals of the motor neurons in third instar larvae. Eye imaginal disc-specific knockdown of dFIG4 induces abnormal morphology of the adult compound eye, the rough eye phenotype. In this study, we carried out modifier screening of the dFIG4 knockdown-induced rough eye phenotype using a set of chromosomal deficiency lines on the second chromosome. By genetic screening, we detected 9 and 15 chromosomal regions whose deletions either suppressed or enhanced the rough eye phenotype induced by the dFIG4 knockdown. By further genetic screening with mutants of individual genes in one of these chromosomal regions, we identified the gene CR18854 that suppressed the rough eye phenotype and the loss-of-cone cell phenotype. The CR18854 gene encodes a long non-coding RNA (lncRNA) consisting of 2566 bases. Mutation and knockdown of CR18854 patially suppressed the enlarged lysosome phenotype induced by Fat body-specific knockdown of dFIG4. Further characterization of CR18854, and a few other lncRNAs in relation to dFIG4 in neuron, using neuron-specific dFIG4 knockdown flies indicated a genetic link between the dFIG4 gene and lncRNAs including CR18854 and hsrω. We also obtained data indicating genetic interaction between CR18854 and Cabeza, a Drosophila homologue of human FUS, which is one of the causing genes for amyotrophic lateral sclerosis (ALS). These results suggest that lncRNAs such as CR18854 and hsrω are involved in a common pathway in CMT and ALS pathogenesis.
•The dFIG4 gene, a Drosophila homologue of human FIG4 is a causing genes for Charcot-Marie-Tooth disease.•The CR18854 gene encoding a long hairpin RNA was identified as a genetic interactant with dFIG4.•The other long non-coding RNA hsrω also genetically interacts with dsss4.•The CR18854 gene genetically interacts with Drosophila FUS (Cabeza), a causing gene for ALS.•The lncRNAs such as CR18854 and hsrω may involve in common pathway for CMT and ALS pathogenesis.