Tingdong Hu
Jiying Liu
Bin Fang
Xue Geng
Qiang Xiong
Lining Zhang
Yong Jin
Xiaorui Liu
Lin Li
Ying Wang
Rongfeng Li
Xiaochun Bai
Haiyuan Yang
Yifan Dai
aJiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 211166, China
bKey Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, China
cDepartment of Cell Biology, Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
dState Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
eShenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
More InformationCorresponding author: E-mail address: hyyang@njmu.edu.cn (Haiyuan Yang);E-mail address: daiyifan@njmu.edu.cn (Yifan Dai)
Publish Date:2020-12-25
Abstract
Abstract
Tuberous sclerosis complex (TSC) is a dominant genetic neurocutaneous syndrome characterized by multiple organ hamartomas. Although rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated, they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans, highlighting the need for an improved large animal model of TSC. Here, we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer (SCNT) technology. The expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets, indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin (mTOR) signaling pathway. Notably, differing from the mouse TSC models reported previously, the TSC1 Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules, resembling the major clinical features that occur in patients with TSC. These TSC1 Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease.Keywords: CRISPR/Cas9,
Cardiac rhabdomyosarcoma,
Subependymal nodules,
Tuberous sclerosis complex
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