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Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors

Molecular Psychiatry volume 21, pages 1417–1433 (2016)Cite this article

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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.

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Acknowledgements

This research was supported by NINDS grants R01 NS073159 (AWB) and R01NS079231 (RYB & NA), the Simons Foundation SFARI #256769 (NA), the Ontario Brain Institute (JPL), and a Autism Speaks Translational Postdoctoral Fellowship #7587 (HB). Behavioral data were obtained with the help of the Gladstone Institute Behavioral Core (supported by NIH grant P30NS065780). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. We thank Peter Scacheri for his critical comments on the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA

    H Belinson, J Nakatani, B A Babineau, M Bershteyn & A Wynshaw-Boris

  2. Department of Life Sciences, Ben-Gurion University at the Negev, Beer-Sheva, Israel

    R Y Birnbaum

  3. Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada

    J Ellegood & J P Lerch

  4. Department of Medicine, Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla, CA, USA

    R J McEvilly & M G Rosenfeld

  5. Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institute of Health, Baltimore, MD, USA

    J M Long

  6. Deparment of Cell and Molecular Biology, Institute for Regenerative Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA

    K Willert

  7. Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA, USA

    O D Klein

  8. Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA

    N Ahituv

  9. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    J P Lerch

  10. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    A Wynshaw-Boris

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  1. H Belinson
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Belinson, H., Nakatani, J., Babineau, B. et al. Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors. Mol Psychiatry 21, 1417–1433 (2016). https://doi.org/10.1038/mp.2015.207

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