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 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Animals
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Behavior, Animal
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Brain / embryology
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Brain / metabolism
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Brain / physiology
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Dishevelled Proteins / genetics
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Dishevelled Proteins / metabolism
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Humans
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Mice
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology
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Neural Stem Cells / metabolism
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Neurons / metabolism
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POU Domain Factors / metabolism
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POU Domain Factors / physiology
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Phosphoproteins / genetics
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Signal Transduction / physiology
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Stereotyped Behavior / physiology
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Stereotypic Movement Disorder / genetics*
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Stereotypic Movement Disorder / physiopathology*
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T-Box Domain Proteins / metabolism
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T-Box Domain Proteins / physiology
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / genetics
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Wnt Signaling Pathway / physiology
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beta Catenin / metabolism
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beta Catenin / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Dishevelled Proteins
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Dvl1 protein, mouse
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Dvl3 protein, mouse
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Eomes protein, mouse
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Nerve Tissue Proteins
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POU Domain Factors
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Phosphoproteins
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T-Box Domain Proteins
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Wnt Proteins
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beta Catenin
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Pou3f2 protein, mouse