Temporal regulation of metamorphic processes in Drosophila by the let-7 and miR-125 heterochronic microRNAs.
BACKGROUND
The let-7 and lin-4 microRNAs belong to a class of temporally expressed, noncoding regulatory RNAs that function as heterochronic switch genes in the nematode C. elegans. Heterochronic genes control the relative timing of events during development and are considered a major force in the rapid evolution of new morphologies. let-7 is highly conserved and in Drosophila is temporally coregulated with the lin-4 homolog, miR-125. Little is known, however, about their requirement outside the nematode or whether they universally control the timing of developmental processes.


RESULTS
We report the generation of a Drosophila mutant that lacks let-7 and miR-125 activities and that leads to a pleiotropic phenotype arising during metamorphosis. We focus on two defects and demonstrate that loss of let-7 and miR-125 results in temporal delays in two distinct metamorphic processes: the terminal cell-cycle exit in the wing and maturation of neuromuscular junctions (NMJs) at adult abdominal muscles. We identify the abrupt (ab) gene, encoding a nuclear protein, as a bona fide let-7 target and provide evidence that let-7 governs the maturation rate of abdominal NMJs during metamorphosis by regulating ab expression.


CONCLUSIONS
Drosophila Iet-7 and miR-125 mutants exhibit temporal misregulation of specific metamorphic processes. As in C. elegans, Drosophila let-7 is both necessary and sufficient for the appropriate timing of a specific cell-cycle exit, indicating that its function as a heterochronic microRNA is conserved. The ab gene is a target of let-7, and its repression in muscle is essential for the timing of NMJ maturation during metamorphosis. Our results suggest that let-7 and miR-125 serve as conserved regulators of events necessary for the transition from juvenile to adult life stages.
Caygill
Elizabeth E
EE
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Johnston
Laura A
LA
D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008675:Metamorphosis, Biological; D035683:MicroRNAs / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development; D009687:Nuclear Proteins / Q000378:metabolism; D014921:Wings, Animal / Q000254:growth & development
D029721:Drosophila Proteins; C531976:Let-7 microRNA, Drosophila; C531977:MIRN125 microRNA, Drosophila; D035683:MicroRNAs; D009687:Nuclear Proteins; C531978:ab protein, Drosophila