A study published in Cell (2024) describes the generation of rat forebrain tissues in mice using an optimized interspecies blastocyst complementation (IBC) strategy based on C-CRISPR. This method enables rapid screening of candidate genes and facilitates the generation of functional rat forebrain tissues in mice. The study identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact, developing at the same pace as the mouse host but maintaining rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late prenatal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis. The study also demonstrated that rat forebrain tissues generated in mice via IBC were structurally and functionally normal, with no significant differences in cognitive functions compared to control mice. However, the chimeric rate of rat cells in mouse forebrain gradually decreased as development progressed, indicating the presence of additional xenogeneic barriers during mid-to-late prenatal development. The study highlights the importance of thoroughly screening and validating candidate genes for creating organ-complemented interspecies chimeras. The findings suggest that both cell-autonomous and non-cell-autonomous mechanisms contribute to organ development within an interspecies context. The study also emphasizes the potential of interspecies neural blastocyst complementation as a transformative approach for studying brain development and disorders. The study has limitations, including the inability to achieve complete replacement of mouse forebrain by rat cells and the need for further research to improve the contribution ratio of rat cells in mouse forebrain. The study also highlights the importance of understanding the interactions between host and donor cells in interspecies chimeras. The study provides insights into the fundamental mechanisms driving brain development, organization, and function. The study also demonstrates the potential of interspecies neural blastocyst complementation for exploring gene regulatory networks, cell-cell communication, and brain functions and behaviors within an evolutionary context. The study has implications for the global shortage of donor organs for transplantation and the potential to expand our understanding of organ development, regeneration, and diseases. The study also highlights the need for further research to develop effective strategies to improve chimeric rates at mid-to-late gestation stages. The study also provides evidence of the functional connectivity between rat and mouse neurons within the chimeric brains. The study also highlights the importance of understanding the intrinsic features of donor cells in interspecies chimeras. The study also emphasizes the potential of interspecies neural blastocyst complementation for exploring the intricate interplay between external factors, like the host environment, and internal factors, such as species-specific geneA study published in Cell (2024) describes the generation of rat forebrain tissues in mice using an optimized interspecies blastocyst complementation (IBC) strategy based on C-CRISPR. This method enables rapid screening of candidate genes and facilitates the generation of functional rat forebrain tissues in mice. The study identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact, developing at the same pace as the mouse host but maintaining rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late prenatal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis. The study also demonstrated that rat forebrain tissues generated in mice via IBC were structurally and functionally normal, with no significant differences in cognitive functions compared to control mice. However, the chimeric rate of rat cells in mouse forebrain gradually decreased as development progressed, indicating the presence of additional xenogeneic barriers during mid-to-late prenatal development. The study highlights the importance of thoroughly screening and validating candidate genes for creating organ-complemented interspecies chimeras. The findings suggest that both cell-autonomous and non-cell-autonomous mechanisms contribute to organ development within an interspecies context. The study also emphasizes the potential of interspecies neural blastocyst complementation as a transformative approach for studying brain development and disorders. The study has limitations, including the inability to achieve complete replacement of mouse forebrain by rat cells and the need for further research to improve the contribution ratio of rat cells in mouse forebrain. The study also highlights the importance of understanding the interactions between host and donor cells in interspecies chimeras. The study provides insights into the fundamental mechanisms driving brain development, organization, and function. The study also demonstrates the potential of interspecies neural blastocyst complementation for exploring gene regulatory networks, cell-cell communication, and brain functions and behaviors within an evolutionary context. The study has implications for the global shortage of donor organs for transplantation and the potential to expand our understanding of organ development, regeneration, and diseases. The study also highlights the need for further research to develop effective strategies to improve chimeric rates at mid-to-late gestation stages. The study also provides evidence of the functional connectivity between rat and mouse neurons within the chimeric brains. The study also highlights the importance of understanding the intrinsic features of donor cells in interspecies chimeras. The study also emphasizes the potential of interspecies neural blastocyst complementation for exploring the intricate interplay between external factors, like the host environment, and internal factors, such as species-specific gene