Critical Window Into Developing Human Brain

Researchers have generated a high-resolution blueprint for how to build a human brain, with a detailed map of where different genes are turned on and off during mid-pregnancy at unprecedented anatomical resolution. This is the first major report using data from the BrainSpan Atlas of the Developing Human Brain.

“Knowing where a gene is expressed in the brain can provide powerful clues about what its role is,” says Ed Lein, Investigator at the Allen Institute for Brain Science. “This atlas gives a comprehensive view of which genes are on and off in which specific nuclei and cell types while the brain is developing during pregnancy. This means that we have a blueprint for human development: an understanding of the crucial pieces necessary for the brain to form in a normal, healthy way, and a powerful way to investigate what goes wrong in disease.”

This paper represents the first major report to make use of data collected for the BrainSpan Atlas of the Developing Human Brain, a big science consortium initiative which seeks to create a map of the transcriptome across the entire course of human development. “Coming on the first anniversary of the BRAIN Initiative, this is a terrific example of the potential for public-private partnerships to accelerate progress in neuroscience,” says Lein.

Thomas R. Insel, Director of the National Institute of Mental Health, praises the BrainSpan Atlas as an already invaluable tool to researchers. “While we have had previous reports of molecular and cellular changes during human brain growth, the BrainSpan Atlas is the first comprehensive map of the dramatic trajectory of gene expression across prenatal and postnatal development,” he says. “This atlas is already transforming the way scientists approach human brain development and neurodevelopmental disorders like autism and schizophrenia. Although the many genes associated with autism and schizophrenia don’t show a clear relationship to each other in the adult brain, the BrainSpan Atlas reveals how these diverse genes are connected in the prenatal brain.”

Spotlight on Autism

Though virtually all developmental diseases and disorders can benefit from increased knowledge about how genes are expressed in the developing brain, the researchers pointed to autism as a disorder with particularly pertinent links to early brain development. The research team used the BrainSpan Atlas to examine a number of genes linked to autism in prior scientific studies during development.

“We used the maps we created to find a hub of genetic action that could be linked to autism — and we found one,” says Lein. “These genes were associated with the newly generated excitatory neurons in the cortex, the area of the brain that is responsible for many of the cognitive features affected in autism such as social behavior. This discovery is an exciting example of the ability of the BrainSpan Atlas to generate meaningful hypotheses about the origins of brain developmental disorders.”

What Makes Humans Unique?

Understanding what makes humans unique involves deciphering a complex puzzle — one that begins during the earliest phases of development. The richness of the BrainSpan Atlas gives scientists a new set of tools to assess how the human brain develops compared to other species.

“We know that some important regions of the genome show striking sequence differences in humans compared to other species. Since where a gene is expressed in the brain can give insight into its function, we can use our map to begin to figure out the roles of those genes in making humans distinct,” says Lein. “Our analysis of the data showed that these genes are enriched in the frontal cortex, as well as in several specific specialized cell types including inhibitory GABAergic interneurons and neurons of the transient subplate zone that serves as a scaffold during early circuit formation. These features are all known to be expanded or show developmental differences in humans compared to other species, so our data gives unprecedented clues about the molecular underpinnings of what makes human neocortex unique.”

A Precious Resource Freely Available

As with all the resources produced at the Allen Institute for Brain Science, sharing the data with the public was a fundamental goal from the very beginning. The BrainSpan Atlas enables researchers around the world to conduct research and ask questions about the early human brain that many would not be able to do otherwise, due to the highly limited availability of prenatal tissues.

“The work behind creating this atlas could not have been done anywhere else,” says Allan Jones, Chief Executive Officer at the Allen Institute for Brain Science. “The scope of the project, and the level of detail in the data we collected, could only be accomplished thanks to the highly collaborative and interdisciplinary project-based approach of the Allen Institute team. And now, since the data are publicly available, the entire scientific community can take advantage of our efforts to drive their own investigations forward and in exciting new directions.”

The founding principal investigators in the consortium behind the BrainSpan project include Ed Lein and Michael Hawrylycz at the Allen Institute for Brain Science, Nenad Sestan and Mark Gerstein at Yale University, Jim Knowles at USC , Pat Levittat at The Saban Research Institute of Children’s Hospital Los Angeles and USC, Dan Geschwind at UCLA, and Bruce Fischl at Massachusetts General Hospital.

Journal Reference:

  1. Jeremy A. Miller, Song-Lin Ding, Susan M. Sunkin, Kimberly A. Smith, Lydia Ng, Aaron Szafer, Amanda Ebbert, Zackery L. Riley, Joshua J. Royall, Kaylynn Aiona, James M. Arnold, Crissa Bennet, Darren Bertagnolli, Krissy Brouner, Stephanie Butler, Shiella Caldejon, Anita Carey, Christine Cuhaciyan, Rachel A. Dalley, Nick Dee, Tim A. Dolbeare, Benjamin A. C. Facer, David Feng, Tim P. Fliss, Garrett Gee, Jeff Goldy, Lindsey Gourley, Benjamin W. Gregor, Guangyu Gu, Robert E. Howard, Jayson M. Jochim, Chihchau L. Kuan, Christopher Lau, Chang-Kyu Lee, Felix Lee, Tracy A. Lemon, Phil Lesnar, Bergen McMurray, Naveed Mastan, Nerick Mosqueda, Theresa Naluai-Cecchini, Nhan-Kiet Ngo, Julie Nyhus, Aaron Oldre, Eric Olson, Jody Parente, Patrick D. Parker, Sheana E. Parry, Allison Stevens, Mihovil Pletikos, Melissa Reding, Kate Roll, David Sandman, Melaine Sarreal, Sheila Shapouri, Nadiya V. Shapovalova, Elaine H. Shen, Nathan Sjoquist, Clifford R. Slaughterbeck, Michael Smith, Andy J. Sodt, Derric Williams, Lilla Zöllei, Bruce Fischl, Mark B. Gerstein, Daniel H. Geschwind, Ian A. Glass, Michael J. Hawrylycz, Robert F. Hevner, Hao Huang, Allan R. Jones, James A. Knowles, Pat Levitt, John W. Phillips, Nenad Šestan, Paul Wohnoutka, Chinh Dang, Amy Bernard, John G. Hohmann, Ed S. Lein. Transcriptional landscape of the prenatal human brain. Nature, 2014; DOI: 10.1038/nature13185

Source: Allen Institute for Brain Science. “A critical window into the developing human brain profiled in Nature.” ScienceDaily. ScienceDaily, 2 April 2014. <www.sciencedaily.com/releases/2014/04/140402133941.htm>.

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