DUF1220 protein domains are highly amplified in the human lineage, show signs of positive selection and, in brain, are highly expressed in regions associated with higher cognitive function. Virtually all DUF1220 domains are primate-specific, with the highest copy number (212) found in humans;mice have only one copy and none of the primate type. The majority of DUF1220 domain sequences are found at 1q21.1, and several reports have found copy number variations in 1q21.1 associated with a number of cognitive diseases including autism, schizophrenia and microcephaly. Given the potential importance of DUF1220 to human cognitive disease and brain evolution, the goal of this application is to develop the first animal model encoding human DUF1220 domains. Two human BAC clones each encoding a different human DUF1220 gene and multiple DUF1220 domains, will be used for the production of transgenic mice. Additional sequences (tauGFP and tau/Tomato) will be added to each construct to allow expression of the gene to be followed in both neuronal cell bodies and axonal projections. The mice will be initially characterized by Western analysis using the anti- DUF1220 antibody we have developed that sees the primate/human-specific DUF1220 domains but not the single DUF1220 domain found in mice. For follow-up characterization, those mice expressing the two DUF1220 transgenes will be used 1) for cross-breeding experiments to increase the DUF1220 copy number to a more human- like level, 2) for high-resolution immunocytochemical analysis of brain expression patterns, and 3) for a series of behavioral tests designed to monitor learning and memory abilities.

Public Health Relevance

This work should generate the first animal model to study the neuronal and behavioral function of DUF1220 domains, sequences that may be important to higher brain function in humans. As a result, these models should increase our understanding of the molecular mechanisms that underlie certain cognitive diseases such as mental retardation and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33MH089917-03
Application #
8339480
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2010-08-18
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$226,004
Indirect Cost
$76,004
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045