Accession Number:
ADA454215
Title:
The Role of the Neurofibromin-Syndecan-CASK Complex in the Regulation of Synaptic Ras-MAPK Signaling and Dendritic Spine Plasticity
Descriptive Note:
Annual rept. 26 Jan 2005-25 Jan 2006
Corporate Author:
BAYLOR COLL OF MEDICINE HOUSTON TX
Personal Author(s):
Report Date:
2006-02-01
Pagination or Media Count:
10.0
Abstract:
NF1 is a common dominant genetic disorder characterized by multiple benign and malignant tumors of neural origin and, often, cognitive deficits in children. How mutations in the NF1 gene lead to severe learning deficits is largely unknown. The objective of this proposal is to test the hypothesis that the newly identified NF1-Syndecan2-CASK signaling complex plays an essential role in the regulation of synaptic Ras-MAPK activity and dendritic spine maturation. Using several siRNAs and dominant negative constructs for NF1 GAP activity to specifically knockdown or inhibit NF1, we have obtained compelling evidence showing that NF1 deficiency indeed leads to abnormal development of dendritic spines and hyperactive Ras-MAPK activity, and furthermore, these deficits can be rescued by overexpression of NF1 GRD I, a central domain of NF1 responsible for its Ras GAP activity. We have also begun to determine whether 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 the Ras-MAPK activity. 15. SUBJECT TERMS NF1, SYNDECAN2, CASK, RAS-MAPK SIGANLING, DENDRITIC SPINES, IMMUNOCYTOCHEMISTY, FRET, PLASTICITY, EPHB2, NF1 KNOCKOUT MICE, DENTATE EXPLANT CULTURES, TIMELAPSE-IMAGING, CONFOCAL MICROSCOPY, RNA INTEREFENCE, DOMINANT NEGATIVE MUTANTS
Descriptors:
- *PROTEINS
- *NEOPLASMS
- *MUTATIONS
- *RECEPTOR SITES(PHYSIOLOGY)
- *DENDRITIC STRUCTURE
- *GENETIC DISEASES
- *IMMUNOCHEMISTRY
- COGNITION
- DEFICIENCIES
- ABNORMALITIES
- CYTOCHEMISTRY
- PHOSPHORUS TRANSFERASES
- MORPHOLOGY(BIOLOGY)
- MATURATION
- NERVE TRANSMISSION
- SPINAL COLUMN
- CHILDREN
- NERVE CELLS
- MICE
- SYNAPSE
- LEARNING
- RIBONUCLEIC ACIDS
Subject Categories:
- Medicine and Medical Research
- Biochemistry
- Genetic Engineering and Molecular Biology