# A novel embryonic transcriptional cascade required for adult social and repetitive behavior

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $456,141

## Abstract

PROJECT SUMMARY/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. It has been hypothesized that abnormal brain development can cause long-term alterations in
brain circuitry that may later manifest in behavioral disorders in the adult. Consistent with this idea, a significant
subset (~25-30%) of autism spectrum disorder (ASD) is associated with a transient but significant increase in
brain size in the first few years of life, leading to abnormal social and other behaviors. In further support of this
hypothesis, we found that Dishevelled Dvl1-/-; Dvl3+/- mutant mice displayed increased neural progenitor cell
(NPC) proliferation during embryonic development via dysregulation of a novel β-catenin/BRN2 transcriptional
cascade associated with adult social/repetitive behavior and brain abnormalities (Belinson et al. 2016).
 We hypothesize that the β-catenin/BRN2 transcriptional cascade regulates NPC proliferation and
differentiation during brain development of mouse, resulting in normal social behavior. Dysregulation of this
cascade results in abnormal social behavior from aberrant neurogenesis during embryogenesis, which
selectively disrupts adult brain structure/function. We propose to address this hypothesis in the mouse by
employing additional Dvl and Brn2 genetic mouse models, comprehensive behavioral analysis, and state-of-
the-art mouse imaging studies, in the following three aims.
 Aim 1. Determine which pathways downstream of the Dvls are responsible for social/repetitive
behaviors and transient embryonic brain enlargement phenotypes. The involvement of β-catenin
implicates the canonical Wnt pathway in embryonic brain enlargement, social/repetitive behaviors, and adult
brain structure/function. To formally prove this, we will use an allelic series of fluorescently-tagged BAC alleles
to genetically determine whether the role of Dvl genes in embryonic brain enlargement, social/repetitive
behaviors, and adult brain structure/function is via the canonical and/or non-canonical Wnt pathways in vivo.
 Aim 2. Determine the spatial/temporal requirements of the β-catenin/BRN2 transcriptional cascade
for adult social/repetitive behavior and transient embryonic brain enlargement. We will use conditional
alleles for Dvl2 and Brn2 as well as brain-specific Cres to genetically determine the spatial/temporal
requirements of the β-catenin/BRN2 transcriptional cascade in embryonic brain enlargement, social/repetitive
behaviors, and adult brain structure/function.
 Aim 3. Determine the newborn, weanling and adult brain regions linked to embryonic brain growth
and social/repetitive behavior. Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies
of adult brains of mice studied in Aims 1 and 2 will used to determine newborn (P0), weanling (3 weeks of age)
and ad...

## Key facts

- **NIH application ID:** 10191047
- **Project number:** 5R01MH114601-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ANTHONY J. WYNSHAW-BORIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,141
- **Award type:** 5
- **Project period:** 2017-09-11 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191047

## Citation

> US National Institutes of Health, RePORTER application 10191047, A novel embryonic transcriptional cascade required for adult social and repetitive behavior (5R01MH114601-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10191047. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*