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 ?-catenin/BRN2 transcriptional cascade associated with adult social/repetitive behavior and brain abnormalities (Belinson et al. 2016). We hypothesize that the ?-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 ?-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 ?-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 ?-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 adult 10-12 weeks of age) brain abnormalities associated with social/repetitive behavior and transient embryonic brain enlargement. These regions will be further investigated.
We have identified a novel, conserved ?-catenin/Brn2 transcriptional cascade that regulates embryonic neural progenitor proliferation in mouse models with adult social behavior deficits and brain abnormalities. Our main hypothesis is that the ?-catenin/BRN2 transcriptional cascade is a key pathway that exquisitely regulates neural progenitor proliferation and differentiation during brain development of mouse and human, resulting in normal social behavior, while dysregulation results in abnormal social behavior. 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. These studies will advance our understanding of the relationship of the ?-catenin/BRN2 transcriptional cascade to embryonic brain enlargement, social/repetitive behaviors, and neonatal-adult brain structure/function. Further study of this cascade will likely provide important insights into mammalian development and behavior. In addition, the conservation of this pathway in humans and its dysregulation in cellular models of human autism spectrum disorder means that our findings will likely have relevance to human neuropsychiatric disorders.
