Finding Provides Clues to How the Human Brain Regulates Its Own Construction, Strategies for Improving Developmental Disorders
Head size in an infant is a marker of proper brain development, which is why pediatricians measure head circumference at every clinic visit during a baby's first year of life. But 1 out of 50 infants have a head circumference that exceeds what a normal growth curve would predict – a possible sign of pressure on the brain or "faulty wiring" that could create cognitive malfunctions as the child grows up.
While scientists already knew some of the genes that contribute to aberrations in brain size, research by Weill Cornell Medical College scientists reveals a new genetic route to megalencephaly, or MEG — a growth and development disorder in which the brain is abnormally large. The findings, published April 6 in Nature Genetics, suggest that it may be possible to disrupt that pathway, reverting infant brains that are growing too large or in an irregular fashion back to more normal development, says the study's co-lead investigator, Dr. M. Elizabeth Ross, a professor of neurology and neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell.
"Previous studies have associated these mutations with various cancers, but this is the first proof that this kind of genetic alteration has a major impact on human brain size, shape and organization during development," Dr. Ross says.
The discovery of the gene mutation by Dr. Ross with colleagues at the University of Washington, the Leeds Institute of Biomedical and Clinical Science in the United Kingdom and elsewhere offers potential therapeutic possibilities. There are investigational cancer drugs that may alter the previously known pathway responsible for MEG, raising hope that similar therapies could help children improve their development and neurological function, she says.
While unusually large head size is not a problem in itself, it can reflect a mismatch of particular types of neurons that disrupts normal organization of these brain cells generated in utero, she says. The research team, which included investigators from five countries, knew that a mutation in the PI3K-AKT signaling pathway is one cause of megalencephaly. Regulation of this pathway is important in apoptosis, or cell death, in cell division and is overactive in a number of cancers, including breast and lung. The pathway also plays a key role in brain growth and development. But scientists knew little about the specifics of which molecules in this complicated pathway affect normal brain growth.
Dr. Ross has long studied a different gene and its protein — cyclin D2 — that is part of the cell-division cycle. She discovered that the protein regulates brain size and organization, and found that inactivating cyclin D2 in mice produces animals with smaller brains (microcephaly). Knowing that, the scientists were surprised to find that infants with a single letter change in their cyclin D2 gene had bigger brains — MEG — not smaller brains.
Dr. Ross and her laboratory team, which included Dr. Kristin Giamanco, a postdoctoral fellow and co-first author on the study, thought the tiny genetic change must make cyclin D2 too active. To find out, Dr. Giamanco made a mini-gene that would provide instructions for a cell to make the mutant form of cyclin D2 and a fluorescent green protein that would identify the cells making the mutated version of cyclin D2. She then compared the effect of introducing normal or mutant versions of cyclin D2 into mouse embryo brains to study how the gene mutation worked.
Dr. Giamanco found signs that the mutant protein both stimulated cell division and blocked the ability of an enzyme, GSK3beta, to tag cyclin D2 for degradation in the cell, leaving more cyclin D2 to actively promote the proliferation of brain cells.
Now the story came together. Scientists knew that an overactive PI3K-AKT pathway can turn off GSK3beta, which places PI3-AKT and cyclin D2 genes in the same signaling pathway. The researchers thought mutations in cyclin D2 alone might be enough to produce megalencephaly, and found this was true in 12 megalencephaly patients who did not have mutations in either PIK3 or AKT proteins. The new findings implicate a different and more direct route from PI3K to the cell cycle in a developing brain, suggesting ways that the system might be brought back into a proper balance, Dr. Ross says.
"This MEG syndrome is rare but teaches us that subtle perturbations of the PI3K-AKT-cyclin D2 pathway can significantly alter the course of brain development," she says. "It is possible that events that influence the activity of this pathway at critical time windows in brain development could contribute to other, more common disorders like those in the autism spectrum or schizophrenia. The more we learn about how the developing brain regulates its own cell growth and differentiation, the better able we will be to optimize each child's developmental potential."