The Role of the Neurofibromin-Syndecan-Cask Complex in the Regulation of Synaptic Ras-MAPK Signaling and Dendritic Spine Plasticity
Abstract
Neurofibromatosis type 1 (NF1) is a common dominant genetic disorder characterized by multiple benign and malignant tumors of neural origin and, often, cognitive deficits in children. The protein encoded by NF1, neurofibromin, contains a GAP domain, known to inhibit Ras-mediated signal transduction, a pathway known to be required for memory formation. This proposal will define the newly identified NP1-Syndecan2-CASK signaling complex in the regulation of synaptic Ras-MAPK activity and dendritic spine maturation. The specific Aims are: 1) To determine whether the NP1-syndecan-CASK signaling complex is an essential negative regulator for synaptic Ras-MAP kinase activity during synaptic maturation. 2) To define the role of the NP1-syndecan-CASK signaling complex in the formation and maturation of dendritic spines. 3) To assess if NF1-deficient cells have an altered capacity to undergo morphological plasticity after spaced depolarizing stimuli, and whether the deficits in morphology can be rescued by manipulating Ras-MAPK signaling. We have made excellent progress on developing several siRNAs and dominant negative constructs for NF1 GAP activity to specifically knockdown or inhibit NF1, and have begun to assess their effects on Ras-MAPK signaling and spine maturation. Furthermore, we have obtained compelling evidence showing that Nf1+/- neurons display hyperactive basal and evoked MAPK activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2005
- Accession Number
- ADA435803
Entities
People
- Gang-yi Wu
Organizations
- Baylor College of Medicine