A view from Drosophila: multiple biological functions for individual microRNAs

Abstract

microRNAs (miRNAs) comprise an extensive class of post-transcriptional regulatory molecules in higher eukaryotes. Intensive research in Drosophila has revealed that miRNAs control myriad developmental and physiological processes. Interestingly, several of the best-studied miRNAs impact multiple biological processes, often by regulating distinct key target genes in each setting. Here we discuss the roles of some of these pleiotropic miRNAs, and their implications for studying and interpreting the roles of miRNAs in gene regulatory networks.

Figure 1. Modes of miRNA regulation

(A) Individual miRNAs often regulate many targets, each of which may contribute subtly to the overall biological function of the miRNA. (B) A miRNA may repress a large network of targets, but the regulation of a specific target may underlie the major phenotypically visible role of the miRNA. Note that this does not necessarily mean that it is quantitatively the most strongly repressed target of the miRNA; depending on the function of the target, a relatively modest change in activity might elicit a mutant phenotype. (C) A miRNA may function in multiple spatial or temporal contexts, and may have different critical targets in each setting.

Figure 2. Processes regulated by Drosophila miR-7

(A) In the eye imaginal disc, miR-7 is expressed in the specified photoreceptors (stippled portion) and promotes their differentiation by inhibiting yan, an Ets domain transcriptional repressor of neural differentiation. (B) miR-7 also promotes the differentiation of chordotonal organs (grey circles) by inhibiting members of the E(spl)-C family of bHLH transcriptional repressors. (C) In the testis, miR-7 represses bam to inhibit differentiation of germline stem cells (GSCs), whilst in the ovary, miR-7 represses the cell cycle regulator dacapo to promote maintenance of GSCs (D).

Figure 3. Processes regulated by Drosophila miR-8

(A) miR-8 prevents neurodegeneration in the brain by limiting levels of the transcriptional corepressor atrophin. (B) Though not demonstrated under endogenous circumstances, miR-8 is able to repress Wg/Wnt signalling in the developing wing and eye by inhibiting of wntless, which encodes a transmembrane protein required for secretion of Wg; it can also repress CG32767, a positive regulator of Wg/Wnt signalling. (C) During larval growth, miR-8 represses the zinc finger protein encoded by u-shaped in the fat body to promote organismal growth. (D) Finally, miR-8 controls the morphology of neuromuscular junctions by acting in muscles to repress enabled, an EVH1/PH domain regulator of synapse development.

Figure 4. Processes regulated by Drosophila miR-9a

(A) During development of the peripheral nervous system, miR-9a prevents ectopic specification of sensory organ bristles (arrows) through repression of the zinc finger transcription factor encoded by senseless (and to a lesser extent via the LIM protein encoded by dLMO). (B) miR-9a also controls margin specification and limits apoptosis in the developing wing through regulation of dLMO (and to a lesser extent, senseless); the dashed portion of the wing represents tissue that fails to develop in the mir-9a mutant.

Figure 5. Processes regulated by Drosophila miR-bantam

The bantam miRNA controls a wide variety of processes. (A) The most overt defect of bantam mutants are their small size due to failure of cell proliferation, although the relevant target(s) are not known. (B) bantam also prevents apoptosis (cross) by repressing hid, which encodes a pro-apoptotic factor. bantam maintains ovarian germline stem cells (C), and limits the scaling growth of dendrites during larval development (D); the targets mediating these functions are not yet known. (E) Finally, bantam maintains the appropriate length of the circadian clock (represented by an activity trace of animal movements across the day) by regulating clock, which encodes a bHLH-PAS transcription factor.