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VPS4B deficiency causes early embryonic lethality and induces signal transduction disorders of cell endocytosis
genesis ( IF 2.4 ) Pub Date : 2021-03-07 , DOI: 10.1002/dvg.23415
Danna Chen 1 , Fei He 1 , Ting Lu 1, 2 , Jin Huang 1 , Meiyi Li 1 , Decheng Cai 1 , Cheng Huang 1 , Dong Chen 3 , Fu Xiong 1, 4, 5
Affiliation  

VPS4B (vacuolar protein sorting 4B), a member of the ATPase associated with diverse cellular activities (AAA) protein family, is a component of the endosomal sorting complexes required for transport machinery which regulates the internalization and lysosomal degradation of membrane proteins. We previously reported that VPS4B is one of the pathogenic genes related to dentin dysplasia type I, although its function was largely unknown. To investigate the role of VPS4B in tooth development, we deleted the Vps4b gene in mice. We found that heterozygous knockout mice (Vps4b+/−) developed normally and were fertile. However, homozygous deletion of the Vps4b gene resulted in early embryonic lethality of Vps4b−/− mice at approximately embryonic day 9.5 (E9.5). To investigate the underlying molecular mechanisms, we examined the molecular functions of VPS4B in vivo and in vitro. Cell experiments showed that VPS4B influenced the proliferation, apoptosis, and cell cycle of transfected human neuroblastoma cells (IMR‐32 cells) with over‐expression or knockdown of VPS4B. Moreover, qRT‐PCR detection showed that the mRNA expression levels of apoptosis‐, cell cycle‐, and endocytosis‐related genes was significantly down or up‐regulated in RNA interference‐mediated knockdown of VPS4B in IMR‐32 cells and Vps4b+/− E12.5 embryos. We accordingly speculated that signal transduction disorders of cell endocytosis are a contributing factor to the prenatal lethality of Vps4b−/− mice.

中文翻译:

VPS4B缺乏导致早期胚胎致死并诱导细胞内吞作用的信号转导障碍

VPS4B(液泡蛋白分选 4B)是与多种细胞活动 (AAA) 蛋白家族相关的 ATP 酶的成员,是调节膜蛋白内化和溶酶体降解的转运机制所需的内体分选复合物的一个组成部分。我们之前报道过VPS4B是与 I 型牙本质发育不良相关的致病基因之一,尽管其功能在很大程度上是未知的。为了研究VPS4B在牙齿发育中的作用,我们删除了小鼠中的Vps4b基因。我们发现杂合基因敲除小鼠 ( Vps4b +/- ) 发育正常且具有生育能力。然而,Vps4b基因的纯合缺失导致早期胚胎致死率Vps4b -/-小鼠大约在胚胎第 9.5 天 (E9.5)。为了研究潜在的分子机制,我们在体内和体外检测了VPS4B的分子功能。细胞实验表明,VPS4B 过表达或敲低 VPS4B 影响转染的人神经母细胞瘤细胞(IMR-32 细胞)的增殖、凋亡和细胞周期。此外,qRT-PCR 检测显示,在 RNA 干扰介导的IMR-32 细胞中 VPS4B 和Vps4b +/-敲低中,凋亡、细胞周期和内吞作用相关基因的 mRNA 表达水平显着下调或上调。E12.5 胚胎。我们因此推测细胞内吞作用的信号转导障碍是导致Vps4b -/-小鼠产前致死率的一个因素。
更新日期:2021-04-24
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