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DOCK1 不足通过 DUSP4-ERK 通路破坏滋养层功能和妊娠结局。

DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.

机构信息

The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.

出版信息

Life Sci Alliance. 2023 Nov 15;7(2). doi: 10.26508/lsa.202302247. Print 2024 Feb.

DOI:10.26508/lsa.202302247
PMID:37967942
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10651491/
Abstract

Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.

摘要

异常的滋养层功能与复发性自然流产、子痫前期和早产等疾病有关，危害母婴健康。然而，其潜在的调控机制尚不清楚。在这项研究中，我们发现复发性自然流产患者胎盘绒毛中 DOCK1 的表达降低，其表达决定了绒毛外滋养层细胞（EVT）的侵袭特性，凸显了 DOCK1 在调节 EVT 功能方面的一个先前未知的作用。此外，DOCK1 缺乏会干扰 DUSP4 的泛素化降解，导致其积累。这会使 ERK 信号通路失活，从而导致 EVT 迁移和侵袭不足。DOCK1 可能通过调节 E3 连接酶 HUWE1 来调节 DUSP4 的泛素水平。体内实验结果证实，DOCK1 抑制剂 TBOPP 通过使 DUSP4/ERK 通路失活导致小鼠流产。总之，我们的研究结果揭示了 DOCK1 通过 DUSP4-ERK 通路在调节 EVT 功能中的关键作用，并为开发治疗因滋养层功能障碍导致的不良妊娠结局的新方法奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/d6ae590d69c0/LSA-2023-02247_Fig9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/d6ae590d69c0/LSA-2023-02247_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/006be36e1d96/LSA-2023-02247_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/420db944cb22/LSA-2023-02247_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/e449f3af20cb/LSA-2023-02247_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/aefb7b4072e1/LSA-2023-02247_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/6742e0fa1f21/LSA-2023-02247_Fig3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/a60d9de60918/LSA-2023-02247_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/2f2746520fe5/LSA-2023-02247_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/7abb20161f2d/LSA-2023-02247_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/b7a3587acb10/LSA-2023-02247_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a08e/10651491/4a0ae4bea98f/LSA-2023-02247_Fig8.jpg
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