title: A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning.
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.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Zoology, University of Wisconsin; 213 Zoology Research Building, 1117 West Johnson Street, Madison, WI 53706, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Wolman
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Roshan A
authors.initials: RA
authors.lastname: Jain
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Kurt C
authors.initials: KC
authors.lastname: Marsden
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Bell
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Julianne
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, 829 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Katharina E
authors.initials: KE
authors.lastname: Hayer
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, 829 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, 1157 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: granatom@mail.med.upenn.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Granato
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D005260:Female; D005820:Genetic Testing / Q000379:methods; D020745:Genome, Archaeal; D007858:Learning / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D017526:Receptor, IGF Type 1; D011266:Pregnancy-Associated Plasma Protein-A