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Enzyme guidance system. An enzyme called protein phosphatase 1 (PP1), which regulates the flow of signals between nerve cells and helps determine the shapes of their receiving branches, depends on a host of other proteins to do its work. Scientists in Paul Greengard’s Laboratory of Molecular and Cellular Neuroscience, using a technique called interaction cloning, have now identified four members of a new class of proteins that bind to PP1 and maneuver it to specific locations within the cell where it is needed. Because the newly discovered proteins work by also binding to structural filaments inside the cell called actin, the researchers named them phosphatase and actin regulators (phactrs) 1 through 4. In studies on rats, Greengard’s team detected high levels of phactr-1 in specific sections of the brain: the cortex, hippocampus and striatum — and there was an especially high concentration of the protein at the synapses of nerve cells, which send and receive messages. The study was carried out with colleagues at Yale University School of Medicine. Greengard is the university’s Vincent Astor Professor.

Proceedings of the National Academy of Sciences, May 2004

Syndrome X scan. Jeffrey Friedman, Jan Breslow and Markus Stoffel have been studying obesity related diseases on the Micronesian island of Kosrae for the past decade. Now they’re using the island population to launch one of the first large scale genome-wide association studies ever undertaken. Using newly developed “gene chip” technology, the scientists will scan the genomes of more than 3,200 individuals — nearly the entire adult population of the island — in hopes of discovering genetic variations associated with obesity, high blood pressure and diabetes. “We’ve been wanting to do this experiment for a long time, but simply didn’t have tools with the needed power and resolution to get detailed genetic answers to define the associations between specific genes and obesity,” says Friedman, the university’s Marilyn M. Simpson Professor and head of the Laboratory of Molecular Genetics. Kosrae is an ideal setting for genetic studies because it has a unique mix of Caucasian and Polynesian ancestry and a clear distribution of obesity.

Scent of a gene. The family of genes responsible for producing odorant receptors in mice is among the largest of any mammal — about 1,000 of an estimated 30,000 genes are devoted to smell. These 1,000 genes encode receptors that are expressed in neurons spread throughout the olfactory epithelium, the lining of the nose that detects odors. Junji Hirota and Peter Mombaerts have now identified a transcription factor — the third to be discovered in mice — called Lhx2, which has a positive regulatory role in olfactory sensory neuron development. Hirota and Mombaerts speculate that Lhx2 may control both odorant receptor gene choice and olfactory sensory neuron development through distinct mechanisms. Mombaerts is head of the Laboratory of Developmental Biology and Neurogenetics.

Proceedings of the National Academy of Sciences, June 2004

Sex and schizophrenia. A team of researchers led by Maria Karayiorgou at Rockefeller and Joseph A. Gogos at Columbia University College of Physicians and Surgeons report on a new schizophrenia susceptibility gene on human chromosome 22. The gene, called ZDHHC8, encodes an enzyme that modifies proteins important for cell-to-cell communication in the brain. Some people with schizophrenia inherit a version of the gene that encodes a defective enzyme. Oddly, female patients with schizophrenia were more likely to inherit the defective gene than males, possibly explaining some of the sex differences observed in the disease. In experiments with mice lacking ZDHHC8, the scientists found that females with one or zero copies of the gene were abnormal with respect to indices of fearfulness and their ability to process sensory stimuli. The researchers conclude that even modest decreases in the levels of proteins expressed by ZDHHC8 may have substantial effects on behavior and the likelihood of schizophrenia. Karayiorgou is head of the Laboratory of Human Neurogenetics.

Nature Genetics, June 2004

Mutation suppression. In the process of translating genetic instructions into proteins, DNA’s code is fed through two molecular machines — the spliceosome, which edits pre-mRNA to create mRNA, and the ribosome, which assembles proteins from mRNA’s instructions. Research from Magda Konarska’s Laboratory of Molecular Biology and Biochemistry now suggests that evolution has provided these two machines with similar strategies for coping with imperfect instructions, or mutations in the genetic code. The scientists identified two new forms of a gene, prp8, that suppress intron mutations during the two-step process by which the spliceosome deletes specific segments of pre-mRNA. Following several lines of biochemical and genetic analysis, they propose that intron mutations are suppressed by altering the equilibrium between the first and second steps of the process, when the spliceosome changes shape.

Molecular Cell, May 7, 2004

Senseless failure. In the 1960s, David Hubel and Torsten Wiesel showed that if one eye is deprived of visual stimulation, competition arises between the neurons processing signals from the eyes, and the brain’s wiring develops abnormally. Now, Rockefeller’s Peter Mombaerts, working with colleagues at Columbia University, shows that a similar phenomenon occurs in the olfactory system. The scientists used gene-targeted mice to study the maturation of glomeruli — structures in the brain’s olfactory bulb where olfactory nerve cells terminate. The researchers found that when the animals are deprived of scents, the glomeruli do not fully mature. Furthermore, there is a sensitive period during the mice’s development during which sensory activity influences the organization of the glomeruli. The specific timing of this sensitive period varies from one odorant receptor to the next.

Science, June 2004

July 16, 2004

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