miR-92b regulates Mef2 levels through a negative-feedback circuit during Drosophila muscle development.
Mef2 is the key transcription factor for muscle development and differentiation in Drosophila. It activates hundreds of downstream target genes, including itself. Precise control of Mef2 levels is essential for muscle development as different Mef2 protein levels activate distinct sets of muscle genes, but how this is achieved remains unclear. Here, we have identified a novel heart- and muscle-specific microRNA, miR-92b, which is activated by Mef2 and subsequently downregulates Mef2 through binding to its 3'UTR, forming a negative regulatory circuit that fine-tunes the level of Mef2. Deletion of miR-92b caused abnormally high Mef2 expression, leading to muscle defects and lethality. Blocking miR-92b function using microRNA sponge techniques also increased Mef2 levels and caused muscle defects similar to those seen with the miR-92b deletion. Additionally, overexpression of miR-92b reduced Mef2 levels and caused muscle defects similar to those seen in Mef2 RNAi, and Mef2 overexpression led to reversal of these defects. Our results suggest that the negative feedback circuit between miR-92b and Mef2 efficiently maintains the stable expression of both components that is required for homeostasis during Drosophila muscle development.
Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, 4029 BSRB, Ann Arbor, MI 48109, USA.
Zhimin
Z
Chen
Shanshan
S
Liang
Ying
Y
Zhao
Zhe
Z
Han
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004330:Drosophila / Q000196:embryology* / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004625:Embryo, Nonmammalian; D025461:Feedback, Physiological / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D009132:Muscles / Q000196:embryology* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D020413:3' Untranslated Regions; D029721:Drosophila Proteins; C576274:MIRN92 microRNA, Drosophila; C499409:Mef2 protein, Drosophila; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors