PUBLICATION
Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1
- Authors
- Wolman, M.A., de Groh, E.D., McBride, S.M., Jongens, T.A., Granato, M., Epstein, J.A.
- ID
- ZDB-PUB-140903-9
- Date
- 2014
- Source
- Cell Reports 8(5): 1265-70 (Journal)
- Registered Authors
- Epstein, Jonathan A., Granato, Michael, Wolman, Marc
- Keywords
- none
- MeSH Terms
-
- Animals
- Cyclic AMP/metabolism*
- Learning*
- MAP Kinase Signaling System
- Memory*
- Neurofibromatosis 1/metabolism*
- Neurofibromatosis 1/physiopathology
- Neurofibromin 1/genetics
- Neurofibromin 1/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- ras Proteins/metabolism*
- PubMed
- 25176649 Full text @ Cell Rep.
Citation
Wolman, M.A., de Groh, E.D., McBride, S.M., Jongens, T.A., Granato, M., Epstein, J.A. (2014) Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1. Cell Reports. 8(5):1265-70.
Abstract
Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder associated with attention deficits and learning disabilities. The primary known function of neurofibromin, encoded by the NF1 gene, is to downregulate Ras activity. We show that nf1-deficient zebrafish exhibit learning and memory deficits and that acute pharmacological inhibition of downstream targets of Ras (MAPK and PI3K) restores memory consolidation and recall but not learning. Conversely, acute pharmacological enhancement of cAMP signaling restores learning but not memory. Our data provide compelling evidence that neurofibromin regulates learning and memory by distinct molecular pathways in vertebrates and that deficits produced by genetic loss of function are reversible. These findings support the investigation of cAMP signaling enhancers as a companion therapy to Ras inhibition in the treatment of cognitive dysfunction in NF1.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping