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
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