Roles of miR-137 in Muscular Dystrophy and Muscular Dystrophy-Related Phenotypes in Drosophila melanogaster

by Shruti Chhetri
Doctoral thesis
Date of Examination:2019-04-04
Date of issue:2019-05-07
Advisor:PD Dr. Halyna Shcherbata
Referee:PD Dr. Halyna Shcherbata
Referee:Dr. Stefan Bonn
Referee:Prof. Dr. Jörg Großhans
Persistent Address: http://dx.doi.org/10.53846/goediss-7435

 

 

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Abstract

English

Muscular dystrophies (MDs) are a group of diseases that cause muscular and neurological disorders in human patients. They are associated with a multi-component complex called the Dystrophin Glycoprotein Complex (DGC). The DGC connects the extracellular matrix to the cytoskeleton and is well-conserved in animals. Perturbation of this complex is associated with various kinds of MDs, leading to a diverse range of muscle and nervous system abnormalities. Dystroglycan (Dg) is a central DGC component, mutations of which are associated with a heterogeneous group of MDs also known as dystroglycanopathies. MiRNAs are small, noncoding RNAs that function in posttranscriptional gene regulation and often represses their target mRNAs. Previous work has shown that similar to MD, stress itself causes muscle degeneration, and altered miRNA expression profiles have been detected in dystrophic as well as stressed wild type flies. These results indicate that miRNAs influence a common regulatory pathway between stress and MD. Though much is known about the DGC and its relevance to MDs, the molecular and genetic pathways underlying MD pathogenesis remain largely unknown. To understand the role of miRNAs in DGC signaling and their contribution to MDs, in particular during stress, we screened several miRNAs that are predicted to target multiple components of the DGC study their potential roles in MD development, particularly upon various stresses. We found that miR-137, miR-966, and miR-927 affect muscle integrity upon stress and aging. Our study further reveals that miR-966 and miR-137 are required more during adult muscle maintenance than developing muscles. MiR-137, in particular, is a stress-responsive miRNA, as the severity of the phenotypes related to muscle maintenance progressed in a stress- and age-dependent manner. We further show that levels of Dg must be regulated to sustain healthy muscle, and this regulation includes targeting of Dg by miR-137. The Dg-miR-137 interaction is required to address negative effects of stress in adult muscle maintenance. Our results also demonstrate that a perturbed blood-testis barrier (BTB) in testes is a novel phenotype related to MD, and miR-137 regulates the expression of Dg in early somatic cells of Drosophila testes to maintain the BTB. Our results highlight the importance of miRNAs in the regulation of the DGC and MD, particularly on muscle maintenance that is accelerated upon stress.
Keywords: miRNAs; Muscular Dystrophy; Indirect Flight Muscle; Spermatogenesis; Drosophila melanogaster
 
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