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RESEARCH BRIEFS
Protein Linked to Major Cause of Mental Retardation Found To Regulate Gene Affecting Growth of NeuronsIn 1999, scientists were surprised to discover the identity of the mutation underlying Rett syndrome, a major cause of mental retardation in girls. They expected to find a gene specifically involved in brain development, but instead discovered the culprit was MeCP2, which is expressed in many cell types where it represses transcription of other genes.Now researchers from Children's Hospital and the Whitehead Institute of Biomedical Research have identified a normal function of the MeCP2 protein: controlling expression in neurons of a gene, BDNF, that plays a key role in neuronal development, survival, and plasticity. The discovery, reported in the Oct. 31 Science, is a significant advance in Rett syndrome research. The scientists believe mutations in MeCP2 impair its ability to regulate genes during a critical stage of brain development. "This deregulation may be responsible for some of the defects we see in Rett patients," said Michael Greenberg, HMS professor of neurology at Children's and a lead author. Rett syndrome affects one of about 15,000 female babies worldwide who suffer from cerebral-palsy and autism-like symptoms along with retardation. The new study is a collaboration between the labs of Greenberg, who studies BDNF regulation, and Whitehead's Rudolf Jaenisch, who created a Mecp2-mutant mouse model of Rett. MeCP2's known role is to permanently silence genes, so the researchers were surprised to discover it playing a more dynamic role in neurons. After BDNF is methylated, MeCP2 binds to it, shutting off BDNF temporarily. If neurons are excited by environmental stimuli, MeCP2 immediately detaches, and BDNF begins producing protein. Mutations in MeCP2 impair its ability to regulate BDNF, and BDNF overexpression may cause Rett. However, "BDNF is probably not the key gene in Rett syndrome," Jaenisch said. "More likely, it's one of many genes." The next step is to identify other genes that are regulated by MeCP2 and thus may be implicated in the disorder.
Protein Appears Crucial to Left-Right AsymmetryResearchers at the Forsyth Institute and other institutions have discovered that a family of proteins known for its role in a variety of cellular mechanisms and diseases also plays a key role in developmental asymmetry.The research team, led by Michael Levin, HSDM assistant professor of oral and developmental biology at Forsyth Institute, demonstrated that the protein family dubbed 14-3-3 is involved in embryonic pattern formation and that left-right asymmetry begins much earlier than was previously believed--within one hour of fertilization. Because the 14-3-3 family is found in fungi, plants, and vertebrates, the study highlights a conservation of signaling mechanisms across distant organisms and links the functional physiology of the three kingdoms. Writing in the Oct. 20, 2003 Development, the researchers point out that 14-3-3 proteins have long been known to affect many aspects of cell development in plants and animals. In mammals, the proteins play diverse roles in cell proliferation, differentiation, and death. In humans, it is used to diagnose mad cow and Creutzfeldt-Jakob diseases, in which prions are believed to act as infectious agents that cause cell function to go awry. "Clearly, 14-3-3 proteins play an important natural role in the cell cycle process," Levin said. "Our research establishes a new function for this family of proteins. Learning more about how 14-3-3s are used to control tissue pattern will be very important in developing new approaches for understanding and treating human ills such as cancer and prion disease. A wider understanding of how 14-3-3 proteins control cell cycle and other parameters will be crucial in targeting cell proliferation and function in such illnesses." According to Levin, the findings will also help explain such conditions as right-left hand preference, mirror-image twins, right- versus left-brain dominance, and birth defects that cause organs to develop on the wrong side of the body. In the study, the scientists found that fusicoccin, a compound produced by fungi to attack plant cells, caused frog embryos to develop some of their asymmetrical organs on the wrong side. In plant cells, fusicoccin complexes with 14-3-3 proteins to activate H+ pumping across the plasma membrane. The researchers found biochemical and molecular genetic evidence that 14-3-3 family proteins are part of the receptor that interacts with fusicoccin in frog embryos, and that perturbation of 14-3-3 protein function results in each organ randomly determining its orientation within the body. The subcellular localization of 14-3-3 proteins and mRNAs revealed novel cytoplasmic destinations and a left-right asymmetry at the first cell division. Using gain-of-function and loss-of-function experiments, the researchers determined that 14-3-3E protein is likely to be an endogenous and extremely early aspect of left-right patterning. Jeremy Green, HMS assistant professor of genetics at the Dana-Farber Cancer Institute, who is not an author on the paper, said, "This is clearly one of the last bridging pieces to connect left-right asymmetry to fundamental cell polarity. We are getting very close to the wellspring of the process." --Anita Harris |
