25 Oct 2001

Entire new classes of molecules don't come along every day, so it is worth noting that the classic triumvirate of RNA-mRNA, tRNA, rRNA-has just gotten a baby brother. Three independent research teams are reporting in tomorrow's Science the discovery of almost 100 different microRNAs in three species and homologs in organisms as diverse as the worm Caenorhabditis elegans, its cousin C. briggsae, zebrafish, the fruit fly, mice, cows, and humans.

Researchers led by Thomas Tuschl of the Max Planck Institute for Biophysical Chemistry in Goettingen, Germany, by David Bartel at the Whitehead Institute in Cambridge, Massachusetts, and Rosalind Lee and Victor Ambros at Dartmouth Medical School in New Hampshire, used a range of biochemical and bioinformatics methods to prospect for tiny RNAs about 22 nucleotides long. (Typical protein-coding mRNAs range from 1,000 to 10,000 nucleotides.)

Until recently, only two such RNAs, lin-4 and let-7 of C. elegans, were known. Hundreds more may be discovered, the scientists write. "Tiny RNA genes may be the biological equivalent of dark matter, all around us but almost escaping detection," writes Gary Ruvkun of Massachusetts General Hospital in an accompanying Perspective article.

The big question is what microRNAs, miRNAs for short, are doing. Lin-4 and let-7 are providing clues. First discovered in the Ambros (Lee et al., 1993) and Ruvkun labs (Reinhart et al. 2000), respectively, these miRNAs regulate gene expression in the nematode embryo. They bind to the 3'untranslated region of particular target mRNAs, which represses further translation of those mRNAs and thus nudges the embryo into the next developmental stage.

The newly discovered microRNAs show great diversity. Some are expressed only during certain developmental stages, others in particular tissues (one, for example, is expressed specifically in human heart), while still others are uniformly expressed. Together with other data, this suggests that microRNAs may prove to be an important class of fast and potent "riboregulators" that direct the post-transcriptional control of genes, the authors write. Such knowledge could become useful in efforts to program the differentiation of stem cells for tissue repair, they add.

In the brain, microRNAs could function in synaptic plasticity, Ruvkun writes. The mRNA for Cam Kinase II, an enzyme implicated in postsynaptic signaling after a synapse has fired, localizes to dendrites and dendritic spines of the postsynaptic neuron (Mayford et al, 1996). Its 3'untranslated region has been sequenced (Mori et al., 2000), and Ruvkun speculates that a miRNA complementary to this sequence might be involved in controlling translation of this kinase.—Gabrielle Strobel

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1. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993 Dec 3;75(5):843-54. PubMed.
2. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000 Feb 24;403(6772):901-6. PubMed.
3. Mayford M, Baranes D, Podsypanina K, Kandel ER. The 3'-untranslated region of CaMKII alpha is a cis-acting signal for the localization and translation of mRNA in dendrites. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13250-5. PubMed.
4. Mori Y, Imaizumi K, Katayama T, Yoneda T, Tohyama M. Two cis-acting elements in the 3' untranslated region of alpha-CaMKII regulate its dendritic targeting. Nat Neurosci. 2000 Nov;3(11):1079-84. PubMed.