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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 β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-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.

Original publication

DOI

10.1038/mp.2015.207

Type

Journal article

Journal

Mol Psychiatry

Publication Date

10/2016

Volume

21

Pages

1417 - 1433

Keywords

Adaptor Proteins, Signal Transducing, Animals, Behavior, Animal, Brain, Dishevelled Proteins, Humans, Mice, Nerve Tissue Proteins, Neural Stem Cells, Neurons, POU Domain Factors, Phosphoproteins, Signal Transduction, Stereotyped Behavior, Stereotypic Movement Disorder, T-Box Domain Proteins, Wnt Proteins, Wnt Signaling Pathway, beta Catenin