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.
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
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes