An intein-split transactivator for intersectional neural imaging and optogenetic manipulation

Hao-Shan Chen, Xiao-Long Zhang, Rong-Rong Yang, Guang-Ling Wang, Xin-Yue Zhu, Yuan-Fang Xu, Dan-Yang Wang, Na Zhang, Shou Qiu, Li-Jie Zhan, Zhi-Ming Shen, Xiao-Hong Xu, Gang Long () and Chun Xu ()
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Hao-Shan Chen: Chinese Academy of Sciences
Xiao-Long Zhang: University of the Chinese Academy of Sciences
Rong-Rong Yang: Chinese Academy of Sciences
Guang-Ling Wang: Chinese Academy of Sciences
Xin-Yue Zhu: Chinese Academy of Sciences
Yuan-Fang Xu: Chinese Academy of Sciences
Dan-Yang Wang: Chinese Academy of Sciences
Na Zhang: Chinese Academy of Sciences
Shou Qiu: Chinese Academy of Sciences
Li-Jie Zhan: Chinese Academy of Sciences
Zhi-Ming Shen: Chinese Academy of Sciences
Xiao-Hong Xu: Chinese Academy of Sciences
Gang Long: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Chun Xu: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The cell-type-specific recording and manipulation is instrumental to disentangle causal neural mechanisms in physiology and behavior and increasingly requires intersectional control; however, current approaches are largely limited by the number of intersectional features, incompatibility of common effectors and insufficient gene expression. Here, we utilized the protein-splicing technique mediated by intervening sequences (intein) and devised an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in multiple-feature defined cell types in mice. We validated the specificity and sufficiency of IBIST to control fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions. The IBIST-based Ca2+ imaging showed that the IBIST can intersect five features and that hippocampal neurons tune differently to distinct emotional stimuli depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and controls common effectors to effectively regulate gene expression, monitor and manipulate neural activities.

Date: 2022
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DOI: 10.1038/s41467-022-31255-x

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