PUBLICATION

A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

Authors
Wolman, M.A., Jain, R.A., Marsden, K.C., Bell, H., Skinner, J., Hayer, K.E., Hogenesch, J.B., Granato, M.
ID
ZDB-PUB-150311-3
Date
2015
Source
Neuron   85(6): 1200-11 (Journal)
Registered Authors
Granato, Michael, Jain, Roshan, Marsden, Kurt, Wolman, Marc
Keywords
none
MeSH Terms
  • Neurons/metabolism
  • Receptor, IGF Type 1/genetics
  • Receptor, IGF Type 1/metabolism*
  • Genetic Testing/methods
  • Behavior, Animal
  • Pregnancy-Associated Plasma Protein-A/genetics
  • Pregnancy-Associated Plasma Protein-A/metabolism*
  • Signal Transduction/genetics*
  • Pregnancy
  • Genome, Archaeal*
  • Female
  • Animals
  • Learning/physiology*
  • Zebrafish/metabolism*
  • Mutation/genetics*
(all 15)
PubMed
25754827 Full text @ 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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nkhspgffdmc131bEtTransgenic Insertion
    p170
      Point Mutation
      p171
        Point Mutation
        p172
          Point Mutation
          p173
            Unknown
            p174
              Point Mutation
              p175
                Unknown
                p176
                  Unknown
                  p177
                    Point Mutation
                    p178
                      Unknown
                      1 - 10 of 16
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      No data available
                      Fish
                      Antibodies
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CitrineEFGCitrine
                      GAL4FFEFGGAL4FF
                      1 - 2 of 2
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                      Mapping
                      No data available