Dissecting the role of Ataxin 2 Binding Protein 1 in sarcomeric protein stoichiometry and generation of muscle diversity in Drosophila melanogaster

Abstract

Drosophila muscles are an excellent model to study muscle development, diversity and function. Drosophila muscles consist of two major types –1. Indirect Flight Muscles (IFM), that are fibrillar; as opposed to other tubular muscles of head, abdomen etc. Ataxin 2 Binding Protein 1 (A2BP1) is a regulator of splicing; it binds to cis-intronic element 5’-UGCAUG-3; and carries out exon skipping and/or retention during splicing. Disruption of A2BP1 function has been associated with muscle disorders - cardiac hypertrophy and facio-scapulo-humoral dystrophy. However, detailed mechanism/s by which A2BP1 contributes to muscle development and physiology is not known. This thesis titled, “Dissecting the role of Ataxin 2 Binding Protein 1 in sarcomeric protein stoichiometry and generation of muscle diversity in Drosophila melanogaster” documents studies revealing novel roles of A2BP1 in generation of muscle diversity its role in progression of muscle disease. Studies on the IFMs show that A2BP1 regulates stoichiometry of Sarcomeric proteins, TnI and Act88F, directly or via transcription factor, Mef2. A2BP1 also regulates fiber specific splicing of Troponin-I. The improper splicing and stoichiometric imbalance in A2BP1 knock-down condition leads to muscle hypercontraction phenotype in the IFMs. Further, A2BP1 is expressed more in tubular muscles. The relative levels of RNA binding proteins- Arrest and A2BP1 are crucial for generating muscle fiber specific isoform profiles. A2BP1 negatively regulates fibrillar fate promoting factors- Extradenticle, Spalt (major) and Arrest, known to be involved in generation of muscle diversity. Identification of fiber specific isoform of Mef2 undergoing A2BP1 dependent splicing explains maintenance of fiber specific sarcomeric protein stoichiometry. This study shows that A2BP1 is a key dissipater of muscle fiber type specific changes during development.