Researchers produce complete map of gene activity in the mouse brain
25 August 2011
The data obtained has been made freely available as an online research resource, which is expected to assist future studies seeking to understand the way the mammalian brain is organised.
Professor Chris Ponting, of the Medical Research Council (MRC) Functional Genomics Unit at the University of Oxford, says: "The brain is the most mysterious of organs. If we are to understand the way it works, we must understand its complex structure.
"Cells in different layers of the brain do different things, and this organisation contributes to our levels of cognition. We've completed a massive sequencing effort to map out which genes are active and in which layers of the cortex. In doing so, we're shining a light on to cognitive processes."
The study is published in the journal 'Neuron' and was funded by the MRC, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council and the US National Institutes of Health.
The researchers used a new sequencing technology called RNAseq, a technology related to the latest DNA sequencers used to decode our genomes, to map gene activity in the different layers of the mouse cerebral cortex.
The RNAseq technique works by sequencing all the RNA molecules in a tissue sample to detect which genes are active. RNA molecules are similar to DNA, but are only produced in a cell when a gene is active. Which genes are active can indicate which biological processes are occurring and are important in those cells.
The cerebral cortex is the largest part of a mammal's brain and is understood to be responsible for memory, sensory perception, language and higher-order cognitive functions. It has been known since the 19th century to have a layered structure, with each of the six layers differing in the types of neurons and connections found there. By determining the gene activity in the six layers, it should be possible to start connecting brain anatomy, genetics and disease processes with much greater precision.
The researchers found that over half of the genes expressed in the mouse brain showed different levels of activity in different layers. This is likely to indicate the areas of the brain in which these genes play an important role.
The findings make it possible to look at where genes previously associated with susceptibility to different diseases act. Genes linked to Parkinson's disease, for example, are particularly active in layer five. While this correlation does not necessarily imply causation, it does indicate one of the new research avenues that are opened up by the study.
The technique is also able to detect 'noncoding RNAs' - RNA molecules, produced from the DNA in between known genes, that do not code for proteins but that may play a critical role in regulating genes and controlling biological processes.
"We see a vast array of noncoding RNAs - hundreds that have never been seen before, but presumably have a biological role to play in the brain," says Professor Zoltan Molnár from the University of Oxford. "One of the most abundant RNAs produced in the mouse brain is a noncoding RNA."
The approach also reveals RNAs that, once read off from the DNA code, are stitched together in different ways through a process called alternative splicing. This process results in different proteins that can have different biological roles, despite coming from the same gene.
Many of the alternatively spliced genes identified showed different distributions of the alternative protein forms between layers. This includes the Mtap4 gene, which has been identified as a candidate gene that could be involved in Alzheimer's disease.
Professor Ponting sees this work as a step towards getting finer and finer detail about gene activity in the brain, as sequencing becomes possible with smaller and smaller samples. "We can look to move from structural layers to different types of neuronal cells and perhaps down to individual neural circuits and cells," he suggests.
The researchers now hope to do similar studies with human brain tissue samples. Studies in mouse models of human diseases such as Parkinson's could also pinpoint differences in gene activity that are important for understanding the biological processes behind those conditions.
Image: Digital artwork of a network of neurons. Credit: Arran Lewis/Wellcome Images
Reference
Belgard TG et al. A transcriptomic atlas of mouse neocortical layers. Neuron 2011 [epub].