I will investigate the role of Reln and Dab1 in the formation of the mammalian visual system. The dendrites of Dab1-positive cells are abnormally arranged in the inner synaptic layer of reeler retina, which lack Reln, and contain more Dab1 protein compared to normal mice. In the reeler superior colliculus, the trajectories of RGC axons are aberrant. These observations suggest that Reln and Dab1 are involved in the formation of the visual system.
Specific Aims 1 and 2 will test the hypothesis that Reln acts as a guidance molecule for growing neurites in the retina and in the midbrain.
Specific Aim 1 examines the phenotype in the reeler retina using immunohistochemical and ultrastructural techniques. In addition, primary retinal cultures will be used to develop in vitro assays to test the role of Reln and Dab1 in neurite outgrowth.
Specific Aim 2 investigates the abnormal trajectory of RGC axons in the reeler superior colliculus. The hypothesis is that Reln is required for the correct targeting of these axons in the superior colliculus. Retinal explants from control and reeler mice will be co-cultured with midbrain slices from either control or reeler mice and the RGC projections will be examined.
Specific Aim 3 investigates the nature of the biochemical pathway linking Reln and Dab1. The specific hypothesis is that Rein activates a phosphorylation-dependent signaling pathway involving Dab1. Dissociated retinal cultures will be prepared from control and reeler mice and will be exposed to purified Reln and control proteins. Alterations in Dab1 levels and phosphorylation states in retinal neurons will be determined biochemically. The results obtained here may also provide insights into the function of these genes in other brain structures.
| Rice, D S; Curran, T (2001) Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 24:1005-39 |
| Rice, D S; Northcutt, G M; Kurschner, C (2001) The Lnx family proteins function as molecular scaffolds for Numb family proteins. Mol Cell Neurosci 18:525-40 |
| Rice, D S; Nusinowitz, S; Azimi, A M et al. (2001) The reelin pathway modulates the structure and function of retinal synaptic circuitry. Neuron 31:929-41 |
| Rice, D S; Curran, T (2000) Disabled-1 is expressed in type AII amacrine cells in the mouse retina. J Comp Neurol 424:327-38 |
| Rice, D S; Curran, T (1999) Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. Genes Dev 13:2758-73 |
