motoneurons in the cerebral cortex, also known as upper motoneurons, control our muscle movement through lower motoneurons in the brain stem and spinal cord. Degeneration of upper motoneurons results in progressive spastic and weakness in muscles, which underlies some debilitating neurological disorders, such as amyotrophic lateral sclerosis (ALS), hereditary spastic hemiplegia and primary lateral sclerosis. There is no effective treatment for these motoneuron disorders, for the most part due to the lack of understanding how cortical motoneurons are born, functionally mature and degenerate. This application, based on our success in producing spinal motoneurons from human embryonic stem cells (ESCs), will explore the feasibility of generating upper motoneurons from self-renewing human ESCs (H1 and H9 lines, NIH Registry WA01 and WA09). We have established a chemically defined culture system to direct human ESCs to neuroepithelial cells and discovered a critical primitive neuroepithelial stage for specification of region-specific neuronal subtypes. We will first induce differentiation of dorsal telencephalic neural progenitors by examining the effect of such morphogens as Wnts, Wnt antagonists, and fibroblast growth factors (FGFs), individually, in combination, or sequentially. These progenitors will then be further differentiated to motoneurons in the presence of neurotrophic factors and/or target cells (lower motoneuron) and/or local environment. The function of in vitro generated upper motoneurons will be assessed by their interaction with lower motoneurons in culture and following transplantation to dorsal telencephalon of a chick embryo. This application will thus produce the currently unavailable upper motoneurons from limitless ESCs and offer an otherwise inaccessible tool for studying how human upper motoneurons are born, functionally mature, and become sick. These cells will also provide a target for screening pharmaceuticals that stop the process of motoneuron degeneration and a source for potential future cell therapy for upper motoneuron related diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS055261-02
Application #
7230108
Study Section
Special Emphasis Panel (ZRG1-NCF (07))
Program Officer
Owens, David F
Project Start
2006-03-01
Project End
2007-10-14
Budget Start
2007-03-01
Budget End
2007-10-14
Support Year
2
Fiscal Year
2007
Total Cost
$70,729
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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