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January 8, 1999 RESEARCH BRIEFS Filamin1 Gene Needed For Nerve Migration In Developing Brain
The discovery that neurons in the cerebral cortex require filamin1--a gene known for its role in blood clotting--to migrate from their birthplace in the ventricular zone to the proper layer in the cortex, surprised researchers Jeremy Fox, graduate student at HMS; Christopher Walsh, associate professor of neurology at HMS and Beth Israel Deaconess; and their collaborators.In fact, after locating the gene's chromosomal position, the researchers ranked filamin1 last on their list of likely candidates. In identifying filamin1's role in neuronal migration, the researchers also identified the genetic cause of a rare disease called periventricular heterotopia (PH). Magnetic resonance imaging (MRI) reveals that the brains of PH patients have structural abnormalities. Walsh says the MRIs show large neurons misplaced in the ventricular zone. Surprisingly, in spite of these obvious defects in brain formation, Walsh says, the patients have normal mental capabilities. Patients do suffer from epilepsy and, as reported in the December Neuron, the mutations in filamin1 also cause blood-related conditions, such as stroke, that were initially overlooked by the researchers. Highly conserved among disparate organisms, filamin1 regulates the cytoskeleton, causing actin to reorganize in response to signals from the extracellular matrix. Walsh suggests that without filamin1, cells cannot change their shapes appropriately in response to the surrounding environment, causing blood clots to form in the wrong places and preventing neurons from migrating. Because the filamin1 gene is on the X chromosome, females can survive with only one good copy, while males with a mutant gene generally die before birth. Feature of Polycystic Ovary Syndrome May Be InheritedIn a preliminary genetic study, researchers have shown that a central biochemical feature of polycystic ovary syndrome (PCOS)--elevated male hormone levels--is most likely an inherited disorder. PCOS affects women by causing disruptions in ovulatory cycles and elevated male hormones. It is associated with infertility, menstrual disturbances, and an increased risk of diabetes. In an effort to determine whether the disorder arises from genetic factors, Andrea Dunaif, associate professor of medicine at HMS and Brigham and Women's Hospital, and her colleagues examined the sisters of women diagnosed with the syndrome. The researchers found that 22 percent of the sisters also had PCOS, indicating that the disorder occurs more frequently in certain families. Interestingly, another 24 percent did not have abnormal menstrual cycles, but did have elevated male hormones. Until this study, researchers had not realized that elevated male hormone levels alone could be present in the sisters of women with PCOS. "No one knew that this was part of the familial manifestation of PCOS. These findings suggest that an underlying genetic defect in ovarian and adrenal male hormone production is an important cause of familial PCOS," says Dunaif. She says a more comprehensive understanding of the disorder should facilitate genetic linkage studies, helping researchers diagnose those affected by faulty genes associated with the syndrome. MCH Knockout Mice Lose Appetite, Speed MetabolismAdding to understanding about the physiological pathways controlling feeding and metabolism, researchers have found that eliminating the neuropeptide melanin-concentrating hormone (MCH) leads to decreased food consumption and increased metabolism in mice. The findings may have implications related to obesity and other eating disorders. Jeffrey Flier, professor of medicine at HMS and Beth Israel Deaconess, with his wife, Eleftheria Maratos-Flier, assistant professor of medicine at HMS and Joslin Diabetes Center, and colleagues deleted the MCH gene in mice using knockout technology. The researchers found that mice lacking MCH weigh 25 percent less than normal mice. Due not only to a decrease in appetite and therefore calories consumed by the thinner mice, but also an increased metabolic rate, the thin mice consumed more oxygen per unit of body mass compared to their normal mice counterparts. Mice lacking MCH also showed a 50 percent reduction in total body fat. The researchers found that knocking out MCH induced changes in other neuropeptides, giving clues about the feedback mechanisms between the genes. Leptin--known for its own knockout phenotype of obesity--decreases, presumably signaling the brain of a need for more food. Another neuropeptide, POMC, which works to suppress appetite, also declines. Because the low leptin and POMC levels do not induce the MCH knockout mice to eat more or regulate their metabolism, Maratos-Flier says the results suggest MCH works downstream of these other neuropeptides in the feeding pathway. MCH is the first example of a neuropeptide whose deletion results in leanness. A previous knockout of the neuropeptide Y gene, which encodes another appetite-stimulating peptide, did not appear to affect feeding, suggesting some redundancy among the genes that regulate eating. Exercise Can Also Strengthen the ElderlyAs a student of physical therapy, David Krebs, lecturer on orthopedic surgery at HMS and MGH, learned that trying to make people stronger in old age was a silly notion. But with research published in the December Archives of Physical Medicine and Rehabilitation, Krebs and his colleagues from Boston University and the New England Research Institutes have dispelled that dogma, showing that moderate exercise can increase the strength of elderly people. The researchers found that seniors performing simple, choreographed exercises with elastic bands for one-half hour three times a week, increased their strength by 17 percent over a six month period. Though only a relatively minor improvement, the change translated into more stable walking. Compared to a control group, seniors doing the exercises walked faster and swayed less from side to side. To provide a broader base of support, elderly people often keep their feet wide apart when walking, but the space between the feet of those seniors doing the exercises decreased. "Many people with disabilities don't realize that exercise can improve their strength. That attitude prevails among older people," Krebs says. But exercising seems to help everyone, and Krebs suggests that improvements in strength may lead to greater independence and participation in community activities. „Briefs above by Judy Silber White Cells Use Their Arms to Slow Down, Make TurnsBlood rockets through vessels--red cells, platelets, and plasma making the round trip at the equivalent of hundreds of miles per hour. Leukocytes hang back at a more leisurely pace, rolling along at about 50 mph as they swing out of the mainstream in the large vessels onto a vascular off-ramp toward a lymph node. Ulrich von Andrian, assistant professor of pathology at HMS and the Center for Blood Research, and his colleagues observed the race through the vessels in mice via intravital microscopy, reporting in the December/January Journal of Experimental Medicine that white cells use arms to grab vessel walls and the distribution of arms determines how well the cells slow down. White cells bearing patches of armlike ligands on the tips of their microvilli had an easier time tethering ligands embedded in the endothelial surface. Those cells turned out to be ten times more likely to tether and roll than ones with randomly distributed arms. Once the cells left the mainstream, the distribution of the arms had no effect on rolling velocity. The paper follows earlier work by von Andrian and his colleagues demonstrating that leukocyte homing depends on the cells'ability to tether and roll along the endothelium. Rolling is the first step in the adhesion cascade that sends the cells down specialized venules and eventually into peripheral lymph nodes. |
