RT Journal Article
SR Electronic
T1 DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302247
DO 10.26508/lsa.202302247
VO 7
IS 2
A1 Xu, Yichi
A1 Liu, Xiaorui
A1 Zeng, Weihong
A1 Zhu, Yueyue
A1 Dong, Junpeng
A1 Wu, Fan
A1 Chen, Cailian
A1 Sharma, Surendra
A1 Lin, Yi
YR 2024
UL https://www.life-science-alliance.org/content/7/2/e202302247.abstract
AB 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.