Editors' ChoiceGene Expression

MicroRNA Keeps the Lid on Notch

STKE  17 May 2005:
Vol. 2005, Issue 284, pp. tw186
DOI: 10.1126/stke.2842005tw186

The critical role of the Notch pathway (which provides signals that control cell fate and tissue differentiation during development) is evident in the multiple redundant mechanisms that restrict inappropriate activity of Notch-dependent gene expression. When CSL transcription factors are not activated by Notch signaling, they actively repress expression of target genes. Various pathway components, including the receptor Notch itself, are regulated by ubiquitin-dependent degradation. Lai et al. explore yet another mechanism and provide evidence of an expanded role for microRNA-mediated regulation in control of Notch-dependent gene expression. In Drosophila, Notch signaling regulates two clusters of genes, the E(spl)-C (enhancer of split-complex) and BRD-C (bearded complex). These genes contain sequence motifs that appear to be complementary to miRNAs, and loss of these sites is found in gain-of-function alleles of some of the genes. Lai et al. used in vivo reporter assays to show that most members of the gene complexes are regulated directly by members of three families of Drosophila miRNAs. Ectopic expression of miRNAs caused mutant phenotypes that resembled those of flies with loss-of-function mutations in the Notch pathway. The results also suggest that the Drosophila miRNAs may fine-tune regulation of target genes rather than switching them on and off as some animal miRNAs do. Furthermore, Lai et al.'s results suggest that functional inhibition is possible without extensive pairing to target mRNA sequences and that some genes encode transcripts with multiple functional miRNA binding sites in the 3′ untranslated region.

E. C. Lai, B. Tam, G. M. Rubin, Pervasive regulation of Drosophila Notch target genes by GY-box-, Brd-box-, and K-box-class microRNAs. Genes Dev. 19, 1067-1080 (2005). [Abstract] [Full Text]