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.
Structural correlates of recurrent collateral interneurons producing both electrical and chemical inhibitions of the Mauthner cell
A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting
Large-scale mutagenesis in the zebrafish: in search of genes controlling development in a vertebrate
Learning of the conditioned eye-blink response is impaired by an antisense insulin-like growth factor I oligonucleotide
Habituation and sensitization of the acoustic startle response in rats: amplitude, threshold, and latency measures
The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A
A mutation in the AMPA-type glutamate receptor, glr-1, blocks olfactory associative and nonassociative learning in Caenorhabditis elegans
Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A
Cell surface targeting of pregnancy-associated plasma protein A proteolytic activity. Reversible adhesion is mediated by two neighboring short consensus repeats
Potentiation of quantal secretion by insulin-like growth factor-1 at developing motoneurons in Xenopus cell culture
Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development
Cell surface adhesion of pregnancy-associated plasma protein-A is mediated by four clusters of basic residues located in its third and fourth CCP module
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Regulation of insulin-like growth factor (IGF) bioactivity by sequential proteolytic cleavage of IGF binding protein-4 and -5
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Triploidy in zebrafish larvae: Effects on gene expression, cell size and cell number, growth, development and swimming performance
Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function
Further characterisation of differences between TL and AB zebrafish (Danio rerio): Gene expression, physiology and behaviour at day 5 of the larval stage
Deep learning-enabled analysis reveals distinct neuronal phenotypes induced by aging and cold-shock.
Quantitative iTRAQ-based proteomic analysis of differentially expressed proteins in aging in human and monkey
A Forward Genetic Screen in Zebrafish Identifies the G-Protein-Coupled Receptor CaSR as a Modulator of Sensorimotor Decision Making.
Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss.
Subcellular Dissection of a Simple Neural Circuit: Functional Domains of the Mauthner-Cell During Habituation.
A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1.
Gaining an understanding of behavioral genetics through studies of foraging in Drosophila and learning in C. elegans.
Developmental exposure to non-dioxin-like polychlorinated biphenyls promotes sensory deficits and disrupts dopaminergic and GABAergic signaling in zebrafish.
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