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

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

SUBMITTER: Belinson H

PROVIDER: S-EPMC5685528 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Belinson H H Nakatani J J Babineau B A BA Birnbaum R Y RY Ellegood J J Bershteyn M M McEvilly R J RJ Long J M JM Willert K K Klein O D OD Ahituv N N Lerch J P JP Rosenfeld M G MG Wynshaw-Boris A A

Molecular psychiatry 20160202 10

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 media ...[more]

PMID: 26830142

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Project description:BackgroundEndocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult.ObjectiveOur goal was to identify gestational EDC exposures associated with autistic behaviors.MethodsWe measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs.ResultsMost of the EDCs were associated with negligible absolute differences in SRS scores (? 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (? = 2.5; 95% CI: -0.6, 5.6) or trans-nonachlor (? = 4.1; 95% CI: 0.8-7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (? = -3.0; 95% CI: -6.3, 0.2), ?-hexachlorocyclohexane (? = -3.3; 95% CI: -6.1, -0.5), or PBDE-85 (? = -3.2; 95% CI: -5.9, -0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (? = -2.0; 95% CI: -4.4, 0.4).ConclusionsSome EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, ?-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors.

Project description:Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. We have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.

Dataset Information

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

Publications

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

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