DYRK TRANSGENIC MICE AS A MODEL FOR DOWN SYNDROME

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DESCRIPTION: (adapted from applicant's abstract) Down Syndrome is the most common genetic disease associated with mental retardation, affecting about 1 in every 800 live births. The syndrome results from triplication of chromosome 21 or a segment of it, and it includes facial abnormalities, heart disease, increased frequency of leukemia, early-onset Alzheimer's disease and mental retardation. The latter is associated with decreased neuronal number and reduced complexity of neuronal processes in many regions of the brain. The entire spectrum of Down Syndrome abnormalities likely results from overexpression of several genes located in a critical region on chromosome 21q22.2, and it is thus a complex trait. However, individual aspects of the syndrome may be attributable to one or few genes. Recently, the human homologue of Drosophila minibrain, also known as Dyrk, has been mapped to the Down Syndrome critical region. Mutant minibrain flies have a reduced number of brain cells, suggesting that the mutated gene encodes a protein involved in neurogenesis. Mammalian Dyrks are dual specificity protein kinases with extensinve similarities to Drosophila Minibrain and to the yeast Yak1 protein kinase involved in cell division. Injection of a YAC containing genomic sequences including the Dyrk gene in transgenic mice causes altered neurogenesis and cognitive impairment, suggesting that Dyrk is involved in the brain abnormalities associated with Down Syndrome. To understand whether Dyrk plays a role in the developmental neuropathology underlying the mental retardation aspect of Down Syndrome, the investigators plan to first analyze in detail the normal pattern of expressionand activity of Dyrk in the developing mouse brain. Second, they will create transgenic mice that transiently and specifically express elevated levels of Dyrk in the proliferative zone of the developing brain. Finally, they will analyze in detail the brains of these mice to ascertain whether reduction in the number of neuronal cells, or other defects reminiscent of Down Syndrome, have occurred as a result of Dyrk overexpression in the brain during the period of neurogenesis. Their transgenic mice may serve as a novel animal model to investigate the molecular basis of mental retardation in Down Syndrome.