DYRK TRANSGENIC MICE AS A MODEL FOR DOWN SYNDROME

Project Details

Description

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.
StatusFinished
Effective start/end date4/1/003/31/03

Funding

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $83,350.00
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development: $83,350.00

ASJC

  • Genetics

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