KCTD10 is involved in the cardiovascular system and Notch signaling during early embryonic development

Kaiqun Ren; Jing Yuan; Manjun Yang; Xiang Gao; Xiaofeng Ding; Jianlin Zhou; Xingwang Hu; Jianguo Cao; Xiyun Deng; Shuanglin Xiang; Jian Zhang

doi:10.1371/journal.pone.0112275

KCTD10 is involved in the cardiovascular system and Notch signaling during early embryonic development

PLoS One. 2014 Nov 17;9(11):e112275. doi: 10.1371/journal.pone.0112275. eCollection 2014.

Authors

Kaiqun Ren¹, Jing Yuan², Manjun Yang², Xiang Gao³, Xiaofeng Ding², Jianlin Zhou², Xingwang Hu², Jianguo Cao⁴, Xiyun Deng⁴, Shuanglin Xiang², Jian Zhang²

Affiliations

¹ Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China; Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Research, Medical School, Nanjing University, Nanjing, P.R. China; College of Medicine, Hunan Normal University, Changsha, P. R. China.
² Key Laboratory of Protein Chemistry and Developmental Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, P. R. China.
³ Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Research, Medical School, Nanjing University, Nanjing, P.R. China.
⁴ College of Medicine, Hunan Normal University, Changsha, P. R. China.

Abstract

As a member of the polymerase delta-interacting protein 1 (PDIP1) gene family, potassium channel tetramerisation domain-containing 10 (KCTD10) interacts with proliferating cell nuclear antigen (PCNA) and polymerase δ, participates in DNA repair, DNA replication and cell-cycle control. In order to further investigate the physiological functions of KCTD10, we generated the KCTD10 knockout mice. The heterozygous KCTD10(+/-) mice were viable and fertile, while the homozygous KCTD10(-/-) mice showed delayed growth from E9.0, and died at approximately E10.5, which displayed severe defects in angiogenesis and heart development. Further study showed that VEGF induced the expression of KCTD10 in a time- and dose-dependent manner. Quantitative real-time PCR and western blotting results revealed that several key members in Notch signaling were up-regulated either in KCTD10-deficient embryos or in KCTD10-silenced HUVECs. Meanwhile, the endogenous immunoprecipitation (IP) analysis showed that KCTD10 interacted with Cullin3 and Notch1 simultaneously, by which mediating Notch1 proteolytic degradation. Our studies suggest that KCTD10 plays crucial roles in embryonic angiogenesis and heart development in mammalians by negatively regulating the Notch signaling pathway.

Publication types

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

MeSH terms

Animals
Cardiovascular System / embryology*
Cardiovascular System / metabolism*
Cell Line
Cullin Proteins / metabolism
Embryonic Development* / genetics
Gene Deletion
Gene Expression Regulation, Developmental / drug effects
Gene Order
Genes, Lethal
Genetic Loci
Heart Defects, Congenital / genetics
Heart Defects, Congenital / pathology
Humans
Mice
Mice, Knockout
Neovascularization, Physiologic / genetics
Potassium Channels, Voltage-Gated / genetics*
Potassium Channels, Voltage-Gated / metabolism
Protein Binding
Proteolysis
Receptors, Notch / metabolism*
Signal Transduction*
Vascular Endothelial Growth Factor A / pharmacology

Substances

Cul3 protein, mouse
Cullin Proteins
KCTD10 protein, mouse
Potassium Channels, Voltage-Gated
Receptors, Notch
Vascular Endothelial Growth Factor A

Grants and funding

This work was supported by the 973 project of Ministry of Science and Technique of China (No. 2010CB529900), the Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (No. 20134486), the program for excellent talents in Hunan Normal University (No. ET13107), and the Construct Program of the Key Discipline of Basic Medicine in Hunan Province. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.