miRNAs and musculature

In an effort to understand the biological function of the microRNA mir1, Drs. Nicholas Sokol and Victor Ambros (Darmouth Medical School) have studied the expression profile, transcriptional regulation and loss-of-function phenotype of Drosophila mir-1 (Dmir-1). Mir-1 is an evolutionarily conserved miRNA, whose expression in mouse and humans is limited to heart and skeletal muscle. Strikingly, their study shows that, in Drosophila embryos, mir-1 expression is not required for mesodermal cell fate decisions or cell proliferation during embryogenesis, but rather, that it appears to act to reinforce and maintain cell identity during times of rapid growth.

The authors find that, as in zebrafish, mouse and humans, Dmir-1 is specifically expressed in muscle cells. Furthermore, they show that Dmir-1 expression is regulated by the promesodermal transcription factor Twist and the promyogenic transcription factor Mef2, thus placing Dmir-1 within established transcriptional networks in muscle. However, the authors find that muscles form normally in embryos in which expression of Dmir-1 has been ablated by gene targeting (Dmir-1 KO). A defect is only revealed when larval growth is initiated by feeding, which triggers paralysis and eventually death of Dmir-1 KO larvae.

Analysis of the mutant larvae after feeding reveals disrupted somatic musculature, strongly suggesting a role for Dmir-1 in the maintenance of muscle integrity and identity in times of stress induced by growth. Dr. Sokol proposes that “Mir-1 could function generally to maintain muscle cell identity by ensuring that mRNAs from promiscuously transcribed nonmuscle genes remain inactive.” Their work adds to the emerging range of functions that miRNAs perform in an organism and advocates the study of loss-of-function mutations in miRNA genes as an essential tool for identifying the biological roles of miRNAs.