The development of the human brain is a massive biological construction project that scientists are still only beginning to understand. From the first few cells of the human embryo, billions of neurons and glia cells must be formed and positioned in exactly the right place with all of the proper connections. Hundreds of genes, chemical signals and growth factors have been found to be foremen and tradesmen on this neurological construction site, and if any one of those workers doesn’t show up for work or does their job incorrectly, the consequences can range from severe mental retardation to prenatal death.
That incredible feat of engineering is the backdrop for a new paper published online Sunday in Nature Genetics by a team of scientists and clinicians led by Kathleen Millen, assistant professor human genetics at the University of Chicago, and William Dobyns, a professor of human genetics, neurology and pediatrics at the University of Chicago Medical Center. For the last 8 years, Millen and Dobyns have been looking at a case where the brain’s construction goes awry: a common birth defect of the brain called Dandy-Walker malformation (DWM). In 2004, they found the first two genes that contribute to some children born with DWM, which can lead to motor delays, mental retardation, hydrocephalus and autism. In their new paper, a third gene is implicated in the development of DWM – and it was not one that the authors expected to find.
The researchers found that people with a missing or defective version of a gene called FOXC1 exhibited the characteristic deformity of Dandy-Walker: an improperly formed cerebellum, the region at the back of the brain that controls coordination, balance and other motor processes. But FOXC1 is not a likely culprit for a brain disorder, as it’s never actually expressed in the brain. Instead, it shows up in embryonic tissue called mesenchyme, which later develops into the skull and membranes that wrap around the brain.
Removing the FOXC1 gene from the developing skull causes an error in the brain’s development that throws off the entire cerebellum. That suggests the skull is more than just a protective capsule for the brain; it actually helps direct the brain’s proper construction. To use the building metaphor, FOXC1 is like an outside consultant who never physically visits the construction site, but calls in important instructions to the foremen and their workers erecting the brain’s structure.
“The developing skull and all the stuff around the brain actually is as important for brain development as the brain itself,” Millen said.
That’s a realization that could inspire new ideas about how to study the way the brain forms and what goes wrong in cases of brain birth defects. One extension that excites Millen and Dobyns is the possible connection between cerebellar development, “master regulator” genes like FOXC1, and autism. In fact, autism was co-diagnosed in a majority of the Dandy-Walker patients they examined for the Nature Genetics paper.
“There was this old idea that once you had some significant birth defect that was your diagnosis, all these separate, discrete diagnoses. That’s just not true. All these developmental disorders are nothing but overlapping Venn diagrams,” Dobyns said. “We have noticed a very substantial overlap between cerebellar under-development and autism.”
For more on the Nature Genetics paper, including the story of how the researchers chased the gene from Dandy-Walker patients to a mouse model that wasn’t created to study the brain and a group of peopel with a rare genetic eye disorder, read the official UofC press release here.