The mirtron miR-1010 functions in concert with its host gene SKIP to maintain synaptic homeostasis

Abstract

Main textMicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression in nearly all cellular pathways 1,2 . Recently, studies have revealed the existence of a non-canonical miRNA maturation pathway 3-5 , whose miRNAs, named mirtrons, arise by splicing of an intron from a host gene 6 . A plethora of introns have been inferred as potential mirtrons 7-9 , yet few have been experimentally validated and their functions, particularly in relation to their host genes, remain poorly understood 10,11 .Here, we show that the mirtron miR-1010 downregulates the nicotinic acetylcholine receptor β2 (nAcRβ2) and subsequently maintains synaptic homeostasis within an optimal range. We found that larvae lacking miR-1010 are unable to properly grow and pupariate. Increase of cortical nAcRβ2 mediated by neural activity elevates the level of intracellular calcium (Ca 2+ ). This high Ca 2+ level activates the calcium/calmodulindependent kinase II (CaMKII) and, further downstream, the transcription factor Adf-1.We reveal that Adf-1 triggers the expression of SKIP, the host gene of miR-1010. SKIP tempers synaptic potential by regulating Shal, a potassium voltage-gated channel protein. MiR-1010 reduces the mRNA level of nAcRβ2 to prevent synaptic potentials from overshooting their optimal range. Our results demonstrate how a mirtron, in concert with its host gene, contributes to maintaining homeostasis.Since their discovery more than two decades ago 12,13 , miRNAs have been established as key cellular micromanagers. Canonical miRNAs are genetically encoded short (18-22 nucleotides) hairpin structures that are processed, after transcription, by the Drosha/Pasha