A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting

Ximeng Han; Zhenqian Zhang; Lingjuan He; Huan Zhu; Yan Li; Wenjuan Pu; Maoying Han; Huan Zhao; Kuo Liu; Yi Li; Xiuzhen Huang; Mingjun Zhang; Hengwei Jin; Zan Lv; Juan Tang; Jinjin Wang; Ruilin Sun; Jian Fei; Xueying Tian; Shengzhong Duan; Qing-Dong Wang; Lixin Wang; Ben He; Bin Zhou

doi:10.1016/j.stem.2021.01.007

A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting

Cell Stem Cell. 2021 Jun 3;28(6):1160-1176.e7. doi: 10.1016/j.stem.2021.01.007. Epub 2021 Feb 9.

Authors

Ximeng Han¹, Zhenqian Zhang², Lingjuan He², Huan Zhu², Yan Li², Wenjuan Pu², Maoying Han³, Huan Zhao², Kuo Liu⁴, Yi Li⁵, Xiuzhen Huang², Mingjun Zhang², Hengwei Jin², Zan Lv², Juan Tang², Jinjin Wang⁶, Ruilin Sun⁶, Jian Fei⁶, Xueying Tian⁷, Shengzhong Duan⁸, Qing-Dong Wang⁹, Lixin Wang¹⁰, Ben He¹¹, Bin Zhou¹²

Affiliations

¹ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
³ School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
⁴ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
⁶ Shanghai Engineering Research Center for model organizations, Shanghai Model Organisms Center, Inc., Shanghai, China.
⁷ Key Laboratory of Regenerative Medicine of Ministry of Education, College of Life Science and Technology, Jinan University, Guangzhou, China.
⁸ Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China.
⁹ Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
¹⁰ Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
¹¹ Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. Electronic address: drheben@126.com.
¹² State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhoubin@sibs.ac.cn.

PMID: 33567267
DOI: 10.1016/j.stem.2021.01.007

Abstract

The use of the dual recombinase-mediated intersectional genetic approach involving Cre-loxP and Dre-rox has significantly enhanced the precision of in vivo lineage tracing, as well as gene manipulation. However, this approach is limited by the small number of Dre recombinase driver constructs available. Here, we developed more than 70 new intersectional drivers to better target diverse cell lineages. To highlight their applicability, we used these new tools to study the in vivo adipogenic fate of perivascular progenitors, which revealed that PDGFRa⁺ but not PDGFRa^-PDGFRb⁺ perivascular cells are the endogenous progenitors of adult adipocytes. In addition to lineage tracing, we used members of this new suite of drivers to more specifically knock out genes in complex tissues, such as white adipocytes and lymphatic vessels, that heretofore cannot be selectively targeted by conventional Cre drivers alone. In summary, these new transgenic tools expand the intersectional genetic approach while enhancing its precision.

Keywords: Cre-loxP; Dre-rox; adipocyte progenitors; fate mapping; intersectional genetics; lineage tracing; lymphatic endothelial cells; white adipocytes.

Publication types

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

MeSH terms

Adipocytes*
Animals
Cell Lineage / genetics
Gene Knockout Techniques
Integrases / genetics
Mice
Mice, Transgenic
Recombinases*

Substances

Recombinases
Integrases