Endothelial deletion of PTBP1 disrupts ventricular chamber development

Hongyu Liu, Ran Duan, Xiaoyu He, Jincu Qi, Tianming Xing, Yahan Wu, Liping Zhou, Lingling Wang, Yujing Shao, Fulei Zhang, Huixing Zhou, Xingdong Gu, Bowen Lin, Yuanyuan Liu, Yan Wang, Yi Liu, Li Li, Dandan Liang () and Yi-Han Chen ()
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Hongyu Liu: Shanghai East Hospital, Tongji University School of Medicine
Ran Duan: Shanghai East Hospital, Tongji University School of Medicine
Xiaoyu He: Shanghai East Hospital, Tongji University School of Medicine
Jincu Qi: Shanghai East Hospital, Tongji University School of Medicine
Tianming Xing: Shanghai East Hospital, Tongji University School of Medicine
Yahan Wu: Shanghai East Hospital, Tongji University School of Medicine
Liping Zhou: Shanghai East Hospital, Tongji University School of Medicine
Lingling Wang: Shanghai East Hospital, Tongji University School of Medicine
Yujing Shao: Shanghai East Hospital, Tongji University School of Medicine
Fulei Zhang: Shanghai East Hospital, Tongji University School of Medicine
Huixing Zhou: Shanghai East Hospital, Tongji University School of Medicine
Xingdong Gu: Shanghai East Hospital, Tongji University School of Medicine
Bowen Lin: Shanghai East Hospital, Tongji University School of Medicine
Yuanyuan Liu: Shanghai East Hospital, Tongji University School of Medicine
Yan Wang: Shanghai East Hospital, Tongji University School of Medicine
Yi Liu: Shanghai East Hospital, Tongji University School of Medicine
Li Li: Shanghai East Hospital, Tongji University School of Medicine
Dandan Liang: Shanghai East Hospital, Tongji University School of Medicine
Yi-Han Chen: Shanghai East Hospital, Tongji University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract The growth and maturation of the ventricular chamber require spatiotemporally precise synergy between diverse cell types. Alternative splicing deeply affects the processes. However, the functional properties of alternative splicing in cardiac development are largely unknown. Our study reveals that an alternative splicing factor polypyrimidine tract-binding protein 1 (PTBP1) plays a key role in ventricular chamber morphogenesis. During heart development, PTBP1 colocalizes with endothelial cells but is almost undetectable in cardiomyocytes. The endothelial-specific knockout of Ptbp1, in either endocardial cells or pan-endothelial cells, leads to a typical phenotype of left ventricular noncompaction (LVNC). Mechanistically, the deletion of Ptbp1 reduces the migration of endothelial cells, disrupting cardiomyocyte proliferation and ultimately leading to the LVNC. Further study shows that Ptbp1 deficiency changes the alternative splicing of β-arrestin-1 (Arrb1), which affects endothelial cell migration. In conclusion, as an alternative splicing factor, PTBP1 is essential during ventricular chamber development, and its deficiency can lead to congenital heart disease.

Date: 2023
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DOI: 10.1038/s41467-023-37409-9

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