The genetic networks affected in neurodevelopmental disorders such as autism are poorly understood. Although mutations in several genes have been linked to autism and mental retardation syndromes, the developmental processes affected by these mutations, and the regulatory pathways in which these genes function are largely unknown. Different mutations in the X-linked human Arx homeobox gene have been associated with a range of developmental disorders from cortical malformations to behavioral dysfunction linked to autism. The Arx knockout male mouse also exhibits defects in brain structure consistent with the most severe human disorders, indicating that ARX acts similarly in these two species. Interestingly, we have recently shown that mutations in alr-1, the C. elegans ortholog of Arx affect related developmental processes, suggesting a remarkable conservation of gene function across phyla. We propose to take advantage of the unique experimental tools available in the mouse and C. elegans model systems to further investigate ARX functions. Specifically, we will: 1. Explore the effects of Arx mutations associated with specific neurodevelopmental disorders on neuronal development and function using both the mouse and C. elegans systems. 2. Explore the functional interactions between ARX and a COUP transcription factor identified as an ALR-1 interactor in C. elegans on neuronal development in the mouse. 3. Exploit the genetic power of C. elegans to rapidly identify ARX interactors, regulators and targets, and begin to explore the roles of their mouse homologs in ARX-mediated neuronal development. These experiments utilizing two model systems in parallel will greatly and rapidly expand our understanding of Arx gene function, and identify potential targets for future therapeutic intervention. Mutations in the Arx homeobox gene result in a wide range of neurodevelopmental disorders such as autism and mental retardation. We will exploit the unique advantages of two experimental systems, the mouse and C. elegans, to investigate how Arx gene mutations affect brain development. This work may allow us to rapidly identify potential new targets for rational drug design. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH077741-02
Application #
7490079
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
2007-09-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$211,950
Indirect Cost
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454