P1.26. INTER-STRAIN CHIMERAS REVEAL NEURODEVELOPMENTAL MECHANISMS OF CORPUS CALLOSUM AGENESIS IN A MOUSE MODEL
Silvestre Sampino1, Marta Ziętek1, Dawid Winiarczyk1, Maria Pia Viscomi1, Dominika Żbikowska1, Joanna Czyrska1, Małgorzata Cybulska1, Elżbieta Wenta-Muchalska1, Agnieszka Bernat2
1 Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology PAS, ul Postępu 36A, Jastrzębiec, Poland
2 Laboratory of Photobiology and Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk & Medical University of Gdansk, Gdansk, Poland
INTRODUCTION: The corpus callosum (CC) is the major axon tract of the eutherian brain, connecting and integrating inter-hemispheric neural activities. Developmental defects leading to CC dysgenesis or agenesis affect 1:4000 children worldwide, however, their etiology and pathogenesis remain poorly understood.
AIM(S): To get insights into developmental mechanisms, here, we investigated CC development in inter-strain chimeras generated by combining stem cells and embryos of the BTBR T+ Itpr3tf/J (BTBR) mouse model of CC agenesis with those of the C57BL6/J (B6) control strain.
METHOD(S): BTBR and B6 embryonic stem cells (ESCs) were first engineered to express a TAU-GFP transgene, and subsequently injected into preimplantation embryos, which were then transferred to female recipients to generate chimeric mice. This approach allowed tracing axonal projections, including the CC, in the brains of BTBR<->B6 chimeras.
RESULTS: We found that ESCs of either strain engraft into the host embryo of the other strain and contribute stochastically to multiple brain areas, neuronal circuits, and non-neuronal brain tissues. The CC was present in the brain of 80% of chimeras obtained from BTBR ESCs engrafted into B6 host, and in 15% of chimeras obtained from B6 ESCs engrafted into BTBR host. Remarkably, we found that BTBR ESC-derived cortical neurons can develop callosal inter-hemispheric axonal projections when engrafted in a B6 host embryo.
CONCLUSIONS: These results highlight the intrinsic ability of BTBR neurons to develop callosal inter-hemispheric projections and suggest the involvement of early-life interactions between callosal neurons and non-neuronal cells in determining midline crossing and CC formation. Overall, this study supports the use of inter-strain chimeric mice to unveil mechanisms underlying brain developmental defects, such as CC agenesis.
FINANCIAL SUPPORT: This research was supported by the National Science Center, Poland (grant no. 2020/39/B/NZ4/02105).