Ectopic expression of Cripto-1 in transgenic mouse embryos causes hemorrhages, fatal cardiac defects and embryonic lethality.
Targeted disruption of Cripto-1 in mice caused embryonic lethality at E7.5, whereas we unexpectedly found that ectopic Cripto-1 expression in mouse embryos also led to embryonic lethality, which prompted us to characterize the causes and mechanisms underlying embryonic death due to ectopic Cripto-1 expression. RCLG/EIIa-Cre embryos displayed complex phenotypes between embryonic day 14.5 (E14.5) and E17.5, including fatal hemorrhages (E14.5-E15.5), embryo resorption (E14.5-E17.5), pale body surface (E14.5-E16.5) and no abnormal appearance (E14.5-E16.5). Macroscopic and histological examination revealed that ectopic expression of Cripto-1 transgene in RCLG/EIIa-Cre embryos resulted in lethal cardiac defects, as evidenced by cardiac malformations, myocardial thinning, failed assembly of striated myofibrils and lack of heartbeat. In addition, Cripto-1 transgene activation beginning after E8.5 also caused the aforementioned lethal cardiac defects in mouse embryos. Furthermore, ectopic Cripto-1 expression in embryonic hearts reduced the expression of cardiac transcription factors, which is at least partially responsible for the aforementioned lethal cardiac defects. Our results suggest that hemorrhages and cardiac abnormalities are two important lethal factors in Cripto-1 transgenic mice. Taken together, these findings are the first to demonstrate that sustained Cripto-1 transgene expression after E11.5 causes fatal hemorrhages and lethal cardiac defects, leading to embryonic death at E14.5-17.5.
Institute of Comparative Medicine &Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
Xiaolin
X
Lin
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China.
Wentao
W
Zhao
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Junshuang
J
Jia
Institute of Comparative Medicine &Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Taoyan
T
Lin
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Gaofang
G
Xiao
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Shengchun
S
Wang
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Xia
X
Lin
Institute of Comparative Medicine &Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.
Yu
Y
Liu
Department of Endocrinology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
Li
L
Chen
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Yujuan
Y
Qin
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Jing
J
Li
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Tingting
T
Zhang
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Weichao
W
Hao
Institute of Comparative Medicine &Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.
Bangzhu
B
Chen
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Raoying
R
Xie
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Yushuang
Y
Cheng
Department of General Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.
Kang
K
Xu
Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Kaitai
K
Yao
Department of Anatomy, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
Wenhua
W
Huang
Institute of Comparative Medicine &Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China.|Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Dong
D
Xiao
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Yan
Y
Sun
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