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Generating genetic diversity in the nervous system

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  • Ian Pitchford
    Public release date: 31-Jul-2002 Contact: Heather Cosel coselpie@cshl.org Cold Spring Harbor Laboratory http://www.cshl.org/ Generating genetic diversity in
    Message 1 of 1 , Aug 1, 2002
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      Public release date: 31-Jul-2002
      Contact: Heather Cosel coselpie@...
      Cold Spring Harbor Laboratory

      Generating genetic diversity in the nervous system

      Scientists from Baylor College of Medicine (Texas, USA) and the Wellcome Trust
      Sanger Institute (Cambridge, UK) have deciphered how neurons can synthesize a
      diverse range of proteins from a relatively limited number of genes - a
      discovery with important implications for understanding how complex neural
      circuitry is formed and maintained throughout our lives.

      A long-standing question in neurobiology is how each of the tens of thousands
      of neurons that populate the mammalian brain are instructed to establish the
      specific connections that give rise to our complex neural networks. Researchers
      postulate that the expression of distinct sets of proteins in each individual
      neuron act as molecular cues to direct the course of each neuron's fate. The
      protocadherin (Pcdh) family of proteins are prime candidates for this job, as
      each individual neuron expresses an overlapping but distinct combination of
      Pcdh proteins.

      In the August 1 issue of Genes & Development, Dr. Allan Bradley and colleagues
      report on their identification of the mechanism of neuron-specific Pcdh
      expression. The Pcdh family of proteins is encoded by three gene clusters
      (Pcdh-a, Pcdh-ß, and Pcdh-g) on human chromosome #5, and mouse chromosome #18.
      The a and g clusters each contain genes with several variable exons (coding
      regions of DNA). Each variable exon can be separately joined to a constant
      region of the gene, thereby creating the genetic blueprint for a Pcdh protein
      that will have a unique variable region and a common constant region.

      Dr. Bradley and colleagues have discovered that that although the Pcdh gene
      clusters share a similar genomic structure to the immunoglobin genes in the
      immune system -- where antibody protein diversity confers antigen-binding
      specificity -- the neuron-specific expression of Pcdh proteins is accomplished
      by an entirely different mechanism.

      As Dr. Bradley explains, "We tested the various models by creating mice with a
      variety of modified alleles. The most intriguing theory was recombination (like
      the immunoglobulin genes), but we found no evidence to support this! Rather it
      appears that diversity is predominately generated using alternative promoters
      and cis-alternative splicing with a low level of trans-splicing."

      The researchers found that each variable exon is under the regulatory control
      of its own promoter (a DNA sequence where RNA polymerase binds to initiate
      transcription of the gene into pre-mRNA). Once transcribed, the pre-mRNA
      transcript then predominantly undergoes an intramolecular reaction, known as
      "cis-splicing," whereby a variable exon is cut out and joined, or "spliced," to
      the constant region of that same pre-mRNA transcript. Ultimately, this process
      enables a neuron to manipulate the Pcdh gene structure to generate a number of
      mRNAs, each containing different variable regions, which will each be
      translated into a unique Pcdh protein.

      This work establishes that through the use of multiple promoters and
      cis-splicing, individual neurons are able to express distinct combinations of
      Pcdh genes, and, in turn, proteins. Further work will delineate how the
      differential expression of Pcdh proteins may underlie the specificity of neural

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