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NEUROLOGY Mutation Suggests Novel Signaling Mechanism in Brain Development Data Support "Protomap" Theory of Cortical Patterning In the Warren Museum on the fifth floor of Countway Library lies the skull of Phineas Gage, probably the most famous railroad foreman in medical history. In 1848, Gage survived a horrific accident: a three-and-a-half-foot iron rod shot through his skull, obliterating much of his left frontal lobe. Astonishingly, he was able to make it to the nearest doctor under his own steam. Unfortunately, the damage caused such a dramatic change in Gage's personality that he soon lost his job, and by all accounts, alienated his friends and family. He died 12 years later from seizures that began shortly after the accident and got progressively worse. "Gage," said Christopher A. Walsh, the Bullard professor of neurology at Beth Israel Deaconess Medical Center and a Howard Hughes investigator, "provided some of the earliest evidence of the role played by the frontal lobe of the human cortex." In patients homozygous for a mutation causing BFPP, a rare inherited disorder of the brain, the frontal and parietal lobes are thinner than normal and are twisted into numerous small folds (polymicrogyria). These deformities appear in the MRI images above taken by Stephen Wong, HMS associate professor of radiology at Brigham and Women's Hospital. The frontal view (left) shows the extent of the polymicrogyria, while the cutaway reveals how thin the cortex is. (Images courtesy of Science) It is through accidents, those caused by people and nature, that scientists have uncovered much about the development and function of this part of the brain--and the knowledge keeps growing. In the March 26 Science, Walsh and colleagues report that they have pinpointed mutations responsible for bilateral frontoparietal polymicrogyria (BFPP), a disorder of the human cortex. The genetic lesions lie in a gene for a heretofore uncharacterized G protein-coupled receptor called GPR56, which, it turns out, is not expressed in the cortex, but deep inside the brain. The findings indicate a novel signaling mechanism is at the root of human cortex development, and they help resolve a longstanding debate about when and where the cortical pattern is laid down. Layers of Damage BFPP, which is inherited in an autosomal recessive fashion, causes the frontal and parietal lobes of the cortex to develop poorly. The normally convoluted, deeply fissured lobes are not as thick as usual, and the fissures, or gyri, are more numerous and noticeably smaller than in a normal brain. Under the microscope, the six-layered structure of the cortex is either unrecognizable or is reduced, usually to only four layers. Patients have problems with gait, language, and mental capacity. They often suffer, as Gage did, from seizures. In 2002, Walsh and colleagues traced the BFPP mutations to a region on chromosome 16. To narrow this region, neonatologist Xianhua Piao, an instructor in pediatrics at Children's Hospital and lead author on the Science paper, used linkage analysis to localize the lesions to a small region with only 27 genes. Piao only had to sequence 17 of these to find the right one; in 22 BFPP patients from 12 different extended families, she found eight unique mutations, all in GPR56. Receptor Design G protein-coupled receptors straddle the cell membrane. Seven transmembrane domains, connected by extracellular and intracellular loops, are buried within this envelope, while N- and C-terminal domains on the outside and inside of the cell, respectively, are available to binding partners. The family is one of the largest in the human genome, making up about one percent of all genes. "Yet this is the first such protein involved in patterning the brain," said Walsh. How it functions in this regard is unclear, but all of the mutations are, curiously, on the extracellular part of GPR56. "One can speculate that a random mutation during human evolution could be the underlying cause of regional cortical enlargement." --Pasko Rakic Two splicing mutations and a frame shift mutation occur near the beginning of the protein and probably result in its total abolition, but four missense mutations occur in the N-terminal domain, and one occurs in an extracellular transmembrane loop. "These data strongly suggest that the extracellular domain acts as a ligand receptor," said Walsh. "This contrasts with previous work that showed G proteins are necessary for mitosis of neuronal precursors in flies and worms, but in those animals, a receptor was never found." Cerebral cortex precursors originate deep within the brain in the ventricles and subventricular zones. Here, progenitors proliferate, giving rise to neurons that then migrate to form the cortex. "A long-held but controversial view suggests that cortical patterning takes place at the level of the dividing cells as opposed to after the neurons are formed," explained Walsh. The theory maintains that the neurons are guided by a "map" bestowed by the progenitor cells. Because patterning is compromised in BFPP, Piao wondered if GPR56 expression might help illuminate the existence of this "protomap." Chris Walsh (on left) and colleagues have pinpointed the mutations responsible for the brain disorder BFPP. Lead author Xianhua Piao (on right), Bernard Chang, and Adria Bodell have localized the mutations to the G protein-coupled receptor GPR56. (Photo by Leah Gourley) Using an antisense probe specific for the mouse homolog, Piao looked for gpr56 mRNA by in situ hybridization. In embryonic mice, the gene was robustly expressed in the ventricles and subventricular zones, but hardly any could be detected in the cortex. Though expression of the gene was substantially weaker after birth, in older animals it was still expressed in those few specialized areas, including the dentate gyrus, where adult neurogenesis is known to occur. The results suggest that events responsible for cortical patterning occur in the proliferative zones, supporting the protomap theory. The results also have intriguing implications from an evolutionary standpoint. The N-terminal end of gpr56 is unique to animals with a cerebral cortex, and mutations in that region primarily affect the frontal and parietal lobes, leaving other cortical regions substantially unscathed. If one mutation could make parts of the cortex smaller, then could another mutation in a human ancestor have made it larger? "One can speculate that a random mutation during human evolution could be the underlying cause of regional cortical enlargement," writes Pasko Rakic of Yale University in an accompanying Science perspective. Thus, evolution of the enlarged frontal lobe, the seat of motor function, social behavior, cognition, language, and problem-solving--in short, most of what makes us human--may have been steered by a protomap that was redrawn by a simple mutation. --Tom Fagan