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

• Published in: Neuron (Cambridge, Mass.) Vol. 85; no. 6; pp. 1200 - 1211
• Main Authors: Wolman, Marc A., Jain, Roshan A., Marsden, Kurt C., Bell, Hannah, Skinner, Julianne, Hayer, Katharina E., Hogenesch, John B., Granato, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2015; Elsevier Limited
• Subjects: Animal behavior; Animals; Behavior, Animal; Danio rerio; Female; Genetic Testing - methods; Genome, Archaeal; Learning - physiology; Mutation; 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; Reflexes; Rodents; Signal Transduction - genetics; Zebrafish; Zebrafish - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.02.025

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. •Genome-wide genetic screen identifies first set of vertebrate learning mutants•pregnancy-associated plasma protein-aa is a novel regulator of habituation learning•PAPP-AA functions as a metalloprotease to promote habituation•PAPP-AA/IGF1R/PI3K/Akt signaling axis as a pharmacological target for learning Through a forward genetic screen in zebrafish, Wolman et al. isolate the first functional vertebrate gene set for habituation learning and identify pregnancy-associated plasma protein aa (PAPP-AA)-regulated IGF signaling as a novel mechanism underlying habituation learning.