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

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

doi:10.1371/journal.pone.0112275

Kaiqun Ren, Jianlin Zhou + Show 10 more

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https://doi.org/10.1371/journal.pone.0112275

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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.

Highlights

KCTD10 is a member of the polymerase delta-interacting protein 1 (PDIP1) gene family [1], which consists of 3 members, PDIP1, KCTD10 and TNFAIP1 [2,3,4,5]
While at E9.5 and E10.5, strong KCTD10 signals were detected in the brain neuroepithelium, the optic vessel, otic vesicle, only weak signals were observed in the heart and the dorsal aorta (DA) (Figs. 1B, C)
These results indicate that KCTD10 might play crucial roles during the mouse angiogenesis and neurogenesis in early embryogenesis

Summary

Introduction

KCTD10 is a member of the polymerase delta-interacting protein 1 (PDIP1) gene family [1], which consists of 3 members, PDIP1, KCTD10 and TNFAIP1 [2,3,4,5]. KCTD10 is inducible by TNF-a, interacts with PCNA and the small subunit (p50) of DNA polymerase d [3]. Promoter analysis showed that KCTD10 can be regulated positively by SP1 and negatively by AP-2 transcription factors [5]. KCTD10 was reported to be regulated by a novel transcription factor ETV1 which is unique to gastrointestinal stromal tumors (GISTs), and RNAi-mediated silencing of KCTD10 increased cell invasion, suggesting that KCTD10 function as a tumor suppressor protein [7]. Reports showed that KCTD10 was highly expressed in human heart, skeletal muscle, and placenta, and may regulate the development of neural tube, neuroepithelium and the dorsal root ganglion in mammals [8], suggesting that this protein may play important roles in tissue development [3,6]

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