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Tiny RNA may be universal regulator of developmental timing in animals

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  • Ian Pitchford
    FOR RELEASE: 1 NOVEMBER 2000 AT 14:00 ET US Massachusetts General Hospital http://www.mgh.harvard.edu/ Tiny RNA may be universal regulator of developmental
    Message 1 of 1 , Nov 1, 2000
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      FOR RELEASE: 1 NOVEMBER 2000 AT 14:00 ET US
      Massachusetts General Hospital

      Tiny RNA may be universal regulator of developmental timing in animals

      Discovery by MGH/Harvard scientists may be key developmental insight
      Researchers at Massachusetts General Hospital (MGH) and Harvard Medical School
      have discovered a tiny RNA gene that may control developmental timing in
      creatures as diverse as fish, sea urchins, mollusks, marine worms, flies,
      nematodes and humans.

      The team led by Gary Ruvkun, PhD, of the MGH Molecular Biology Department, a
      professor of Genetics at Harvard Medical School, showed that a tiny regulatory
      RNA that controls developmental timing in the C. elegans nematode worm is
      present in the genomes of a wide variety of animals and is regulated in a
      similar manner.

      The discovery that a universally conserved gene may control developmental
      timing could prove to be a fundamental insight for developmental biology, the
      study of how multicellular creatures control the complex choreography of cells
      as they grow from a fertilized egg into an adult organism. The study appears in
      the Nov. 2 issue of Nature.

      The team was composed of postdoctoral fellows Amy Pasquinelli, PhD, Brenda
      Reinhart, PhD, and a worldwide group of biologists who are experts in the
      biology of marine mollusks, jellyfish, coral, sponges, worms, flies, mice,
      fish, sea urchins and sea squirts.

      By analyzing the genes of this Noah's ark of creatures, the team found that
      this RNA gene is universal to bilaterally symmetric animals (those in whom the
      left and right sides of the body are essentially identical) but is not present
      in more primitive animals, such as sponges and coral, nor in plant or microbial
      species. An RNA gene is one that ultimately leads to the production of the
      single-strand molecule RNA instead of a protein.

      The discovery of this common feature of developmental timing suggests that this
      tiny RNA gene evolved almost a billion years ago in animals to regulate the
      transition from early larval stages to later reproductive phases and that
      almost all animal species have inherited the gene from this common ancestor.

      Because the gene has been conserved over all these years, it is likely to
      regulate features of development that are common to all animals. The discovery
      was greatly aided by the now nearly complete human and fruit fly genome

      Earlier this year the Ruvkun team published in the Feb. 24 issue of Nature the
      discovery in C. elegans of the let-7 regulatory RNA, a 21-nucleotide molecule
      that regulates temporal transitions during the development of the worm.

      This regulatory RNA gene, which is switched on as the animal matures from a
      larval to adult stage and is necessary for this transition, can base pair -
      that is, form a double strand of RNA - with the messenger RNAs from other
      timing control gene, which suppresses their activity.

      In the current report, the Ruvkun team used genome sequence searches to detect
      perfect matches to the let-7 RNA in the Drosophila (fruit fly) and human genome
      databases. They then showed that humans and flies also express this
      21-nucleotide RNA and that in flies and zebrafish these tiny RNA genes are
      turned on only at late stages of development, just as in C. elegans.

      In a broad sampling of animals, they found that the let-7 regulatory RNA also
      is expressed only at later stages in mollusks and annelid worms and is absent
      in more primitive animals - such as jellyfish, coral, and sponge - and in
      non-animal species (plants and microbes). The team also found that the major
      RNA target of let-7 RNA is also conserved in flies and zebrafish, as are the
      specific elements in the target RNA that form base pairs with the let-7 RNA.

      The paper makes a strong case that the let-7 regulatory RNA acts universally in
      animal development to trigger a major temporal transition, from larval to adult
      forms, in many species. While humans and other mammals do not have larval
      stages, it is possible that their let-7 RNA genes could regulate such
      developmental transitions as the "molting" of baby teeth or the growth of
      certain tissues at puberty. Defects in developmental timing could figure in a
      variety of human birth defects.

      The let-7 gene is the type that is missed by current methods of genome sequence
      analysis, Ruvkun explains. For example, estimates of the number of human genes
      vary from 25,000 to 100,000 mostly because current methods of detecting genes
      in the vast expanse of chromosomes are very primitive. Most gene-finding
      computer programs focus on the detection of protein-coding DNA segments, the
      most common form of gene. But there are thousands of known genes that encode
      RNA rather than protein products.

      Genes that encode RNAs are the most primitive, since before protein-coding
      genes evolved, life was dominated by RNA genes in what has been dubbed the "RNA
      World." Even today, protein-coding genes depend on the ribosome, an ancient
      RNA-based enzyme, for the translation of messenger RNA into protein.

      Genes encoding RNAs as short as 21 nucleotides, such as let-7 RNA, are the
      easiest to miss in the analysis of genome sequences. In the case of the let-7
      regulatory RNA, it was genetic analysis in the worm that identified the gene
      and comparative analysis of genome sequences that revealed its universality.

      As more genome sequences emerge, such global comparisons of sequences will
      reveal other regulatory genes by finding long regions of DNA conserved among
      disparate animal genomes. These analyses should reveal the remnants of the RNA
      world that genomes still carry. The paper from the Ruvkun lab also demonstrates
      how comparison of genome sequence databases from a few very diverse organisms
      can catalyze discovery in quite distant species.

      The discovery of the broad role of the let-7 regulatory RNA may be a fundmental
      step in developmental biology. An analogous universal control gene called the
      homeobox, which encodes a protein that binds to DNA, was discovered in fruit
      flies in 1984. That discovery led to a renaissance in developmental biology in
      both vertebrate and invertebrates that continues to this day.

      Similarly, the discovery of how broadly the let-7 timing RNA is conserved
      across the animal kingdom - from worms to flies to mice to humans - will
      trigger further study of how timing is regulated.

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