Genetic profiling reveals genes active in the earliest brain circuit construction

Long before the brain's neurons can facilitate life's big decisions, they have to find their own destiny in the rapidly developing embryo.

In the lingo of neurobiologists, they are "fated" very early on to become certain types of cells, over time traveling to and organizing the various structures that compose the brain. These earliest developments are difficult to observe, like the first few moments in the life of the universe following the Big Bang. But by adapting new tools of genetic profiling, researchers at Rockefeller University have peered into the brain as it's born and teased out genes that shape its aboriginal fate.

Last month in Cerebral Cortex, researchers published a list of 229 genes that they found to be active at the beginning of neurogenesis, specifically those involved in so-called subplate neurons, which form the initial scaffolding for assembling cortical circuits. The genes include a substantial network related to estrogen, a sex hormone whose prominence in the brain differentiates female from male. "That these sex pathways are involved from the get-go is a particular surprise," says Mary E. Hatten, Frederick P. Rose Professor and head of the Laboratory of Developmental Neurobiology. "The research provides a new starting point for people to say, 'what, exactly, are all of these new pathways doing?'"

The experiments, conducted by former graduate student Hilleary Osheroff, now at the American Museum of Natural History, drew on a project developed by Hatten and Nathaniel Heintz, James and Marilyn Simons Professor and head of the Laboratory of Molecular Biology, called the Gene Expression Nervous System Atlas (GENSAT). GENSAT pioneered a genetic engineering technology that employs bacterial artificial chromosomes to visualize the contribution of thousands of genes to the mouse brain with the enhanced green fluorescent protein.

Osheroff screened these genes for involvement in the earliest stages of brain development, when the first neurons begin to stratify across six layers that form the scaffolding of the embryonic brain inside a folding neural tube. Using fluorescence-activated cell sorting, Osheroff isolated the neurons destined for the layer known as the subplate from the Cajal-Retzius neurons, which carry on beyond the subplate to the layer known as the marginal zone. She identified 229 genes specifically dedicated to developing the subplate neurons and found that they were involved in a broad range of activities including cortical development, cell and axon motility, protein trafficking, steroid hormone signaling and central nervous system degenerative diseases.

The work indicates the breadth of factors involved in the early development of neurons and provides investigators with a biochemical handle to start investigating the various contributions, says Hatten. "It's a roadmap, not an answer," she says. "These results could really change the direction of research."

Cerebral Cortex online: April 27, 2009: Gene Expression Profiling of Preplate Neurons Destined for the Subplate: Genes Involved in Transcription, Axon Extension, Neurotransmitter Regulation, Steroid Hormone Signaling, and Neuronal Survival
Hilleary Osheroff and Mary E. Hatten