title: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.
abstract: Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.
authors.affiliation: 1] Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA [2] Interdisciplinary Graduate Program in Molecular and Cellular Biology, The University of Iowa, Iowa City, IA, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Sowers
authors.forename: L
authors.initials: L
authors.lastname: Loo
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Campbell
authors.forename: J D
authors.initials: JD
authors.lastname: Ulrich
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Paemka
authors.forename: T
authors.initials: T
authors.lastname: Wassink
authors.forename: K
authors.initials: K
authors.lastname: Meyer
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authors.initials: X
authors.lastname: Bing
authors.forename: H
authors.initials: H
authors.lastname: El-Shanti
authors.forename: Y M
authors.initials: YM
authors.lastname: Usachev
authors.forename: N
authors.initials: N
authors.lastname: Ueno
authors.forename: J R
authors.initials: JR
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authors.forename: R J
authors.initials: RJ
authors.lastname: Manak
authors.forename: A J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: P J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: B W
authors.initials: BW
authors.lastname: Darbro
authors.forename: G B
authors.initials: GB
authors.lastname: Richerson
authors.forename: D P
authors.initials: DP
authors.lastname: Mohapatra
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authors.lastname: Wemmie
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authors.initials: AG
authors.lastname: Bassuk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D003214:Conditioning, Classical; D003712:Dendrites / Q000648:ultrastructure*; D005106:Exploratory Behavior; D005239:Fear; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D060588:LIM Domain Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008297:Male; D018782:Maze Learning; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000235:genetics; D020125:Mutation, Missense; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D017354:Point Mutation; D057907:Post-Synaptic Density / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012919:Social Behavior; D060449:Wnt Signaling Pathway
chemical_list: D060588:LIM Domain Proteins; D008565:Membrane Proteins; C000588606:PRICKLE2 protein, human; C518732:Prickle2 protein, mouse; D011993:Recombinant Fusion Proteins