Posted by Thomas Insel, Director NIMH (US National Institute of Mental Health)
We are still very much in the discovery phase of neuroscience. Like early explorers of the New World, two papers published this week in Nature provide the first maps of the molecular development of the human brain. Both use human post-mortem brain tissue to study development and for both, development means the changing level of messenger RNA (mRNA) expression across time. The paper from Sestan and colleagues looks at 16 brain areas from 57 individuals. Kleinman and colleagues map RNA expression in the prefrontal cortex from 269 subjects. The results are similar and surprising in many ways.
While we have had previous glimpses of the differences in gene expression across development, the magnitude of the differences here is staggering. Roughly 90% of the genes that are expressed show a difference across region and/or age. The human fetal brain is responsible for most of this variation. Nearly 60% of the genes expressed in the cortex were differentially expressed in fetal life. Not only was there more or less gene expression in the fetal brain, 83% of genes showed differential splicing in the fetus, suggesting different protein products during this early stage of development. When you consider the magnitude of these developmental changes relative to the differences observed between brain regions or between brain and non-brain tissue in adulthood, it appears that the fetal and post-natal brains are different organs with different functions.
The importance of this difference has not been lost on the Kleinman group. In previous studies they have claimed that genetic variations associated with schizophrenia or bipolar disorder may target those specific sites that are enriched in the fetal human brain. But in this new report of prefrontal cortex, they fail to find global relationships between variation in DNA sequence and patterns of RNA expression. Remarkably changes in mRNA expression across early development are mirrored by reciprocal changes in late life.
As with all voyages of discovery, these first reports are mostly calls for further exploration. And anyone can explore. Both studies provide access to a treasure trove of data that can now be mined by others. The prefrontal cortex genetic variability data are available to qualified researchers at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v1.p1 , with the gene expression data accessible at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE30272. They can be explored with a new interface tool at www.libd.org/braincloud. Results of the Sestan project are available from www.humanbraintranscriptome.org, and as part of the BrainSpan database (http://www.developinghumanbrain.org), housed at the Allen Institute for Brain Sciences. For any given gene, these projects will reveal where and when it is expressed throughout the human cortex and other key regions.
Of course, these reports are just a beginning. As with the first maps from the Human Genome Project, it was the subsequent maps of human variation that helped to identify pathways to disease and new potential targets for treatment. There is much more to learn about normal and abnormal brain development, including the role of DNA variation in coding for individual differences in gene expression. We have previously described brain development with changes in size, connections, synaptic density, or neurochemistry. Mapping brain development by changes in gene expression gives us a new level of precision and raises new possibilities for understanding the mechanisms of neurodevelopmental disorders.
Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, Colantuoni EA, Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE. Nature. 2011 Oct 26;478(7370):519-23. doi: 10.1038/nature10524. PMID:22031444
Spatio-temporal transcriptome of the human brain. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M, Sousa AM, Pletikos M, Meyer KA, Sedmak G, Guennel T, Shin Y, Johnson MB, Krsnik Z, Mayer S, Fertuzinhos S, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner A, Reimers M, Kleinman JE, Sestan N. Nature. 2011 Oct 26;478(7370):483-9. doi: 10.1038/nature10523. PMID:22031440