Generation of rat forebrain tissues in mice

Jia Huang; Bingbing He; Xiali Yang; Xin Long; Yinghui Wei; Leijie Li; Min Tang; Yanxia Gao; Yuan Fang; Wenqin Ying; Zikang Wang; Chao Li; Yingsi Zhou; Shuaishuai Li; Linyu Shi; Seungwon Choi; Haibo Zhou; Fan Guo; Hui Yang; Jun Wu

doi:10.1016/j.cell.2024.03.017

Generation of rat forebrain tissues in mice

Cell. 2024 Apr 25;187(9):2129-2142.e17. doi: 10.1016/j.cell.2024.03.017.

Authors

Jia Huang¹, Bingbing He¹, Xiali Yang², Xin Long³, Yinghui Wei⁴, Leijie Li⁵, Min Tang⁶, Yanxia Gao⁴, Yuan Fang⁴, Wenqin Ying⁴, Zikang Wang⁴, Chao Li⁴, Yingsi Zhou⁴, Shuaishuai Li⁴, Linyu Shi⁷, Seungwon Choi⁶, Haibo Zhou⁸, Fan Guo⁹, Hui Yang¹⁰, Jun Wu¹¹

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
² Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China.
³ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
⁴ Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Huidagene Therapeutics Co., Ltd, Shanghai 200131, China.
⁸ Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: hbzhou@ion.ac.cn.
⁹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: guofan@ioz.ac.cn.
¹⁰ Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: huiyang@ion.ac.cn.
¹¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jun2.wu@utsouthwestern.edu.

PMID: 38670071
DOI: 10.1016/j.cell.2024.03.017

Abstract

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and 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. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal 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.

Keywords: C-CRISPR; interspecies blastocyst complementation; interspecies chimeras; interspecies forebrain blastocyst complementation; interspecies neural blastocyst complementation; interspecies organogenesis; rat-mouse chimeras.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blastocyst / metabolism
CRISPR-Cas Systems / genetics
Clustered Regularly Interspaced Short Palindromic Repeats / genetics
Female
Male
Mice
Mice, Inbred C57BL
Organogenesis
Prosencephalon* / embryology
Prosencephalon* / metabolism
Rats
Transcriptome