ABSTRACT
Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a ß-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the ß-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.
Subject(s)
Stereotypic Movement Disorder/genetics , Stereotypic Movement Disorder/physiopathology , Adaptor Proteins, Signal Transducing/genetics , Animals , Behavior, Animal , Brain/embryology , Brain/metabolism , Brain/physiology , Dishevelled Proteins/genetics , Dishevelled Proteins/metabolism , Humans , Mice , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/physiology , Neural Stem Cells/metabolism , Neurons/metabolism , POU Domain Factors/metabolism , POU Domain Factors/physiology , Phosphoproteins/genetics , Signal Transduction/physiology , Stereotyped Behavior/physiology , T-Box Domain Proteins/metabolism , T-Box Domain Proteins/physiology , Wnt Proteins/metabolism , Wnt Signaling Pathway/genetics , Wnt Signaling Pathway/physiology , beta Catenin/metabolism , beta Catenin/physiologyABSTRACT
The autism susceptibility candidate 2 gene (AUTS2) has been associated with multiple neurological diseases including autism spectrum disorders (ASDs). Previous studies showed that AUTS2 has an important neurodevelopmental function and is a suspected master regulator of genes implicated in ASD-related pathways. However, the regulatory role and targets of Auts2 are not well known. Here, by using ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) and RNA-seq on mouse embryonic day 16.5 forebrains, we elucidated the gene regulatory networks of Auts2. We find that the majority of promoters bound by Auts2 belong to genes highly expressed in the developing forebrain, suggesting that Auts2 is involved in transcriptional activation. Auts2 non-promoter-bound regions significantly overlap developing brain-associated enhancer marks and are located near genes involved in neurodevelopment. Auts2-marked sequences are enriched for binding site motifs of neurodevelopmental transcription factors, including Pitx3 and TCF3. In addition, we characterized two functional brain enhancers marked by Auts2 near NRXN1 and ATP2B2, both ASD-implicated genes. Our results implicate Auts2 as an active regulator of important neurodevelopmental genes and pathways and identify novel genomic regions that could be associated with ASD and other neurodevelopmental diseases.
