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Splicing factor Scaf6/CHERP regulates muscle and nervous system development in Drosophila

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posted on 20.04.2020 by Shao-Yen Kao, Keshika Ravichandran, Rippei Hayashi, Maria Spletter

Alternative splicing, the RNA-regulating process that promotes diversity of transcriptome and proteome from the single one gene . Alternative splicing has been views as important role in muscle and nervous development. Taking muscle development as example, different spliced isoforms can have distinct functions in transcription or Ca2+ signaling or confer the sarcomere with distinct contractile properties. Thus, proper regulation of alternative splicing is critical to establish muscle system during development, and mis-regulation of splicing results in diseases such as myotonic dystrophy, dilated cardiomyopathy or spinal motor atrophy. Up to dated, less than 10% of possible regulators of alternative splicing in muscle are studied in muscle. We identify a U2-associated component proteins, Scaf6/DmCHERP in Drosophila muscle system. In vertebrate cell culture, CHERP has been shown as a U2-associated component necessary for the suppression of cryptic splicing and regulate colorectal tumorigenesis. We find that Scaf6 is expressed and plays an essential functional role in Drosophila muscle, as muscle-specific RNAi as well as whole-animal mutants are flightless. We show that the flight defect arises developmentally, as the flight muscle fibers are detached and atrophic from 48 h after puparium formation. Furthermore, loss-of-function of Scaf6 in muscle disrupts spontaneously muscle contraction during muscle development in puparium stage, with has been studied its importance in muscle maturation. Interestingly, we find that Scaf6 has distinct phenotypes in muscle and neurons, as neuronal-specific RNAi results in climbing, grooming, eclosion, axon morphology defects in thorax. Our mRNA-Seq data demonstrates a function for Scaf6 in alternative splicing and the suppression of cryptic splicing specifically in muscle. Our results demonstrate a function for Scaf6 in multiple Drosophila tissues, highlighting the importance of alternative splicing during myogenesis and suggesting pleotropic functions for vertebrate CHERP.

Funding

Identification of Bruno function and direct-targets in muscle development

Deutsche Forschungsgemeinschaft

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EXC 114:  Munich Center for Integrated Protein Science (CIPSM)

Deutsche Forschungsgemeinschaft

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History

Program Number

869B

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