A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila

Abstract

Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co-transcribed Drosophila miRNAs, let-7 and miR-125, non-redundantly regulate a common target, the transcription factor Chronologically Inappropriate Morphogenesis (Chinmo). We first characterize novel adult phenotypes associated with loss of both let-7 and miR-125, which are derived from a common, polycistronic transcript that also encodes a third miRNA, miR-100. Consistent with the coordinate upregulation of all three miRNAs in aging flies, these phenotypes include brain degeneration and shortened lifespan. However, transgenic rescue analysis reveal separable roles for these miRNAs: adult miR-125 but not let-7 mutant phenotypes are associated with ectopic Chinmo expression in adult brains and are suppressed by chinmo reduction. In contrast, let-7 is predominantly responsible for regulating chinmo during nervous system formation. These results indicate that let-7 and miR-125 function during two distinct stages, development and adulthood, rather than acting at the same time. These different activities are facilitated by an increased rate of processing of let-7 during development and a lower rate of decay of the accumulated miR-125 in the adult nervous system. Thus, this work not only establishes a key role for the highly conserved miR-125 in aging. It also demonstrates that two co-transcribed miRNAs function independently during distinct stages to regulate a common target, raising the possibility that such biphasic control may be a general feature of clustered miRNAs.

Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System

“…Many of these miRNAs also exhibited overlapping cellular functions, contributing to processes such as tumorigenesis [23][24][25][26][27][28][29][30], differentiation [31][32][33], proliferation [34][35][36][37][38], apoptosis [39][40][41][42], and cell cycle regulation [34,43,44]. A subset of the miRNAs was associated with nervous system-specific processes, such as differentiation [45][46][47][48][49], lifespan [50], neurite guidance [51][52][53], or synaptogenesis [54][55][56]. We were specifically interested in miRNAs known to contribute to neuronal differentiation and/or axonal guidance, processes that are known to be regulated by RA [10,57].…”

No evidence of functional co-adaptation between clustered microRNAs

“…The 'drift-draft' model is based on the observation that a majority of microRNA clusters are formed during evolution by the random emergence of novel microRNAs near existing microRNA genes in the genome. Although functional co-adaptation may explain some observed patterns in specific microRNA clusters (see for instance (Chawla et al 2016)), the evidence presented so far does not indicate that this is a widespread phenomenon. Here I show that the results presented by Wang et al (2016) do not support the conclusion that clustered microRNAs target overlapping sets of genes more than expected by chance, and therefore, there is no evidence of functional co-adaptation of clustered microRNAs.…”

Circadian clock genes are differentially modulated during the daily cycles and chronological age in the social honeybee (Apis mellifera)

“…It is suggested that let-7 forms a regulatory cycle in the circadian clock being activated indirectly by CLK/CYC through the ecdysteroid pathway and negatively regulates the expression of cwo . Further, let-7 , miR-8 , and miR-34 are essential players in preventing neurodegeneration process and aging in D. melanogaster (Liu et al 2012a, b;Chawla et al 2016). miR-92a has an oscillatory expression in circadian neurons of fruit flies and modulates the neuronal excitability through regulation of sirt2 (Chen and Rosbash 2016).…”