RRC ID 75745
Author Wolman MA, Jain RA, Marsden KC, Bell H, Skinner J, Hayer KE, Hogenesch JB, Granato M.
Title A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning.
Journal Neuron
Abstract Habituation represents a fundamental form of learning, yet the underlying molecular genetic mechanisms are not well defined. Here we report on a genome-wide genetic screen, coupled with whole-genome sequencing, that identified 14 zebrafish startle habituation mutants including mutants of the vertebrate-specific gene pregnancy-associated plasma protein-aa (pappaa). PAPP-AA encodes an extracellular metalloprotease known to increase IGF bioavailability, thereby enhancing IGF receptor signaling. We find that pappaa is expressed by startle circuit neurons, and expression of wild-type but not a metalloprotease-inactive version of pappaa restores habituation in pappaa mutants. Furthermore, acutely inhibiting IGF1R function in wild-type reduces habituation, while activation of IGF1R downstream effectors in pappaa mutants restores habituation, demonstrating that pappaa promotes learning by acutely and locally increasing IGF bioavailability. In sum, our results define the first functional gene set for habituation learning in a vertebrate and identify PAPPAA-regulated IGF signaling as a novel mechanism regulating habituation learning.
Volume 85(6)
Pages 1200-11
Published 2015-3-18
DOI 10.1016/j.neuron.2015.02.025
PII S0896-6273(15)00140-3
PMID 25754827
PMC PMC4368495
MeSH Animals Behavior, Animal Female Genetic Testing / methods Genome, Archaeal* Learning / physiology* Mutation / genetics* Neurons / metabolism Pregnancy Pregnancy-Associated Plasma Protein-A / genetics Pregnancy-Associated Plasma Protein-A / metabolism* Receptor, IGF Type 1 / genetics Receptor, IGF Type 1 / metabolism* Signal Transduction / genetics* Zebrafish / metabolism*
IF 14.415
Zebrafish hspGFFDMC130A