The proposed research utilizes a model of impaired neurodevelopment in the ferret that presents as a thin and disrupted cerebral cortex, with ectopic clusters of cells typical of cortical dysplasia. During generation of the earliest born neocortical layers, treatment with the antimitotic agent, methylazoxy methanol (MAM), disrupts radial glia, and results in abnormally situated Cajal Retzius cells. Features of the brain resulting from this treatment are an excellent model for study of migration defects. The current proposal investigates the following questions resulting from this model. (1) What causes the radial glia to become disorganized? (2) What prevents cells from migrating effectively into the neocortex? (3) What causes the Cajal Retzius cells to become disorganized? The hypothesis is that a radialization factor is present in normal cortex, and when it is provided to MAM-treated cortex, normal radial glial morphology can be restored. A second, related hypothesis is that the restoration of normal radial glial morphology can improve migration in MAM-treated cortex. These hypotheses will be tested and the biochemical nature of the radialization factor will be defined using organotypic and cell cultures and migration bioassays to analyze this system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062721-05
Application #
6878036
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Sieber, Beth-Anne
Project Start
2001-03-15
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2008-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$185,250
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Rockville
State
MD
Country
United States
Zip Code
20817
Poluch, Sylvie; Juliano, Sharon L (2010) Populations of radial glial cells respond differently to reelin and neuregulin1 in a ferret model of cortical dysplasia. PLoS One 5:e13709
Schaefer, Alisa; Poluch, Sylvie; Juliano, Sharon (2008) Reelin is essential for neuronal migration but not for radial glial elongation in neonatal ferret cortex. Dev Neurobiol 68:590-604
Poluch, Sylvie; Juliano, Sharon L (2007) A normal radial glial scaffold is necessary for migration of interneurons during neocortical development. Glia 55:822-30
Gierdalski, Marcin; Sardi, Sergio Pablo; Corfas, Gabriel et al. (2005) Endogenous neuregulin restores radial glia in a (ferret) model of cortical dysplasia. J Neurosci 25:8498-504
Hasling, Thomas A; Gierdalski, Marcin; Jablonska, Beata et al. (2003) A radialization factor in normal cortical plate restores disorganized radial glia and disrupted migration in a model of cortical dysplasia. Eur J Neurosci 17:467-80
Gierdalski, Marcin; Juliano, Sharon L (2003) Factors affecting the morphology of radial glia. Cereb Cortex 13:572-9