Denoising feedback loops by thresholding--a new role for microRNAs.

It is almost axiomatic that precision in spatial and temporal control of gene expression is important for organogenesis. Our appreciation of this notion derives in part from studies of the developing sensory nervous system in Drosophila (for review, see Modolell 1997). In this issue of Genes & Development, Gao and coworkers (Li et al. 2006) add an exciting new twist to this story, showing that post-transcriptional gene regulation by the microRNA miR-9a plays an important role in ensuring the precision of sense organ specification in Drosophila. microRNAs (miRNAs) have gained considerable attention recently as negative post-transcriptional regulators of gene expression (e.g., Ambros 2004; Bartel and Chen 2004; Zamore and Haley 2005; Valencia-Sanchez et al. 2006). miRNAs are an abundant class of noncoding RNAs in animals (Bartel 2004; Berezikov et al. 2005; Xie et al. 2005) and are predicted to target 30% or more of all animal protein coding genes (Brennecke et al. 2005; Grun et al. 2005; Krek et al. 2005; Lewis et al. 2005; Xie et al. 2005). Likewise, a large number of genes—the so-called anti-targets—are under evolutionary pressure to avoid target sites (Farh et al. 2005; Stark et al. 2005). The investigation of such target and anti-target signatures for miRNAs has recently led to the proposal that miRNAs confer robustness to gene expression (Stark et al. 2005; Hornstein and Shomron 2006), yet few definite functions have been assigned to individual miRNAs to date (Li and Carthew 2005; Krutzfeldt et al. 2005; Sokol and Ambros 2005; Giraldez et al. 2006; Teleman et al. 2006; pre-2005 work reviewed in Ambros 2004; Alvarez-Garcia and Miska 2005). Li et al. (2006) now report on the function of miR-9a by generating a targeted knockout of the precursor hairpin in Drosophila melanogaster. miR-9a belongs to a highly conserved family of miRNAs found in worms, flies, and vertebrates. In flies, three highly related miR-9 genes have been identified, but during embryogenesis miR-9a is the only one with strong and detectable expression (Aravin et al. 2003; Stark et al. 2005). Flies lacking miR9a are viable and fertile, but produce extra sense organs. One of the interesting features of this phenotype is that it is variable both in terms of the number of individuals affected and the severity of the defect. Up to 40% of mutant embryos show one or more segments with extra larval sense organs. Similarly, ∼40% of adults show extra mechanosensory organs (bristles in the wing margin or on the thorax). Careful analysis indicates that these extra sense organs do not arise through cell fate changes within the highly stereotypic sense organ lineage, converting one cell type to another. Instead, Li et al. (2006) provide evidence that the extra sense organs reflect the specification of additional sense organ precursors (SOPs) within existing proneural clusters. How does this happen? Animal nervous systems derive from neurectodermal progenitor cell populations. Within these populations, subsets of cells are selected to become neurons and glia, whereas the remainder become epidermal. The fundamental mechanisms by which cells are selected and specified to differentiate as neural precursors are conserved in vertebrate and invertebrate embryos (for review, see Bertrand et al. 2002). In Drosophila, sense organ primordia are initially defined as small clusters of cells that express the “proneural” genes, a family of basic helix–loop–helix (bHLH) transcription factors that are essential for neuronal cell fate determination. When these clusters are first specified, the level of proneural gene expression is low, and all cells in a cluster have the capacity to become the SOP. Typically, only one of these cells is selected to become the SOP in a process that involves lateral inhibition through the Notch signaling pathway (for review, see Artavanis-Tsakonas et al. 1999; Bertrand et al. 2002). Selection of the SOP is thought to result from a slight increase in the level of proneural proteins relative to surrounding cells. This leads to increased expression of the zinc-finger transcription factor Senseless, which in turn feeds back positively on proneural gene expression in the presumptive SOP (Nolo et al. 2000). High levels of proneural gene expression in the SOP cell increase the expression of senseless and of the Notch ligand Delta, which activates Notch in surrounding cells of the cluster. Notch signaling leads to repression of proneural gene expression in these cells through bHLH repressors of the E(spl) complex, working together with low levels of Senseless (Jafar-Nejad et al. 2003). Present addresses: Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02141, USA and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Corresponding author. E-MAIL Stephen.Cohen@embl-heidelberg.de; FAX 49-6221-387-166. Article is online at http://www.genesdev. org/cgi/doi/10.1101/gad.1484606.