Abstract

During the development of the mammalian brain the majority of neurons migrate away from their sites of origin to regions where they become integrated into functional networks. A number of genes that regulate discrete migration events have been identified. Failures in neuronal migration can lead to diseases ranging in severity from epilepsy to mental retardation. ? ? My lab investigates the genes that encode components of a signaling cascade that regulate neuronal positioning, including an extracellular ligand, Reelin; two receptors, ApoER2 and VLDLR; and a cytoplasmic docking protein, Dab1. This signaling pathway regulates the positioning of neurons in several brain regions including the cerebral cortex, the hippocampus, and the cerebellum. We have worked to extend the understanding of the components of the pathway. Using a genetic test in Drosophila we demonstrated antagonism between the amyloid precursor protein (APP) family members and mouse Dab1. ? ? We have recently tested for genetic interactions between Dab1 and APP in mouse development, using a hypomorphic Dab1 allele generated in the lab. We found that overexpression of APP lead to a worsening of the Dab1 hypomorphic phenotype. In contrast, loss-of -function APP partially rescued the mild Dab1 phenotype. This provides evidence that the APP gene, which is involved in Alzheimer?s disease, influences a molecular pathway that controls brain development. We are currently working to determine the molecular mechanism that leads to this genetic interaction. ? ? We have generated a conditional allele for Dab1 and are using this to understand the role of Dab1 in the postnatal development of the cerebellum. In particular we are interested in whether Purkinje cells, which require Dab1 for migration during embryogenesis, require Dab1 during repositioning in the expanding cerebellum after birth. To investigate this we will inactivate the Dab1 gene at various times after birth and examine the cerebella of these animals for any Purkinje cell ectopias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002987-07
Application #
7324625
Study Section
(NGB)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2006
Total Cost
Indirect Cost

  Institution

Name
National Institute of Neurological Disorders and Stroke
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Pramatarova, Albena; Chen, Kelian; Howell, Brian W (2008) A genetic interaction between the APP and Dab1 genes influences brain development. Mol Cell Neurosci 37:178-86
Matsuki, Tohru; Pramatarova, Albena; Howell, Brian W (2008) Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis. J Cell Sci 121:1869-75
Andrade, Nuno; Komnenovic, Vukoslav; Blake, Sophia M et al. (2007) ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin. Proc Natl Acad Sci U S A 104:8508-13
Palazzolo, Isabella; Burnett, Barrington G; Young, Jessica E et al. (2007) Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet 16:1593-603
Hoe, Hyang-Sook; Tran, Tracy S; Matsuoka, Yasuji et al. (2006) DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. J Biol Chem 281:35176-85
Pramatarova, Albena; Ochalski, Pawel G; Lee, Chi-Hon et al. (2006) Mouse disabled 1 regulates the nuclear position of neurons in a Drosophila eye model. Mol Cell Biol 26:1510-7
Dey, Nandini; Howell, Brian W; De, Pradip K et al. (2005) CSK negatively regulates nerve growth factor induced neural differentiation and augments AKT kinase activity. Exp Cell Res 307:1-14
Verbeek, D S; Knight, M A; Harmison, G G et al. (2005) Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting. Brain 128:436-42
Chen, Kelian; Ochalski, Pawel G; Tran, Tracy S et al. (2004) Interaction between Dab1 and CrkII is promoted by Reelin signaling. J Cell Sci 117:4527-36
Strasser, Vera; Fasching, Daniela; Hauser, Christoph et al. (2004) Receptor clustering is involved in Reelin signaling. Mol Cell Biol 24:1378-86

Showing the most recent 10 out of 14 publications