Dr. Silvestre Sampino
Researcher
Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Poland
Chimeric mice reveal neurodevelopmental mechanisms of corpus callosum agenesis in the BTBR mouse model
14/10/2025 – ore 12:00
Abstract:
The etiology and pathogenesis of neurodevelopmental disorders are unclear, with evidence supporting a combination of genetic factors and environmental insults affecting neurodevelopmental trajectories during fetal life. Using the BTBR T+ Itpr3tf/J (BTBR) mouse model of idiopathic autism and corpus callosum agenesis, we examined the maternal and embryonic factors contributing to offspring neurodevelopment and the programming of autism-like behaviors in offspring obtained after reciprocal embryo transfer between the BTBR and the C57BL/6J (B6) control strain. Additionally, we generated BTBR↔B6 chimeric mice by aggregating TAU-GFP-labeled BTBR embryonic stem cells (ESCs) with B6 preimplantation embryos, examining the contribution of cells from each strain to specific structures within the chimeric brains. BTBR conceptuses displayed fetal and placental growth restriction, accompanied by changes in placental histological architecture, transcriptome, and metabolism compared to the B6 control. The autism-like behavioral phenotype characteristic of the BTBR strain remains unchanged after embryo transfer to B6 female recipients. In chimeras, BTBR ESc cells were able to integrate into B6 preimplantation embryos and contribute to several organs and tissues, including the brain. Intriguingly, the majority of chimeric brains showed a normal neuroanatomy, including the presence of a corpus callosum derived from BTBR cells, indicating that BTBR ESc acquire the potential to form callosal projections when engrafted into B6 host embryos. Overall, these studies demonstrate that the peculiar autism-like behavior of BTBR mice is innate and not dependent on the maternal environment provided before birth, and highlight the potential role of prenatal fetus-mother metabolic adaptations through the placenta in determining neurodevelopmental outcomes. Moreover, our results demonstrate that BTBR neurons possess the intrinsic capability to form callosal projections suggesting the implication of non-neuronal cells/tissues in the neuropathogenesis of corpus callosum agenesis.
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