Silencing of dedicator of cytokinesis ( DOCK DOCK 180) obliterates pregnancy by interfering with decidualization due to blockage of nuclear entry of autoimmune regulator ( AIRE AIRE )

摘要

Problem Dedicator of cytokinesis ( DOCK 180) involved in cytoskeletal reorganization is primarily a cytosolic molecule. It is recently shown to be nuclear in HeLa cells but its nuclear function is not known. Method of study The spatiotemporal distribution of DOCK 180 in uterus was studied in uterine cytoplasmic and nuclear compartments during the “window of implantation.” The functional significance of nuclear DOCK 180 was explored by homology modeling, co‐immunoprecipitation assays, and mass spectrometric analysis. Dock180's role in early pregnancy was ascertained by Dock 180 silencing and subsequent quantitative real‐time PCR and Western blotting analysis. Results Our study shows a nuclear DOCK 180 in the uterus during “window of implantation.” Estrogen and progesterone mediate expression and nuclear translocation of DOCK 180. The nuclear function of DOCK 180 is attributed to its ability to import autoimmune regulator ( AIRE ) into the nucleus. Silencing of Dock180 inhibited AIRE nuclear shuttling which influenced its downstream targets, thereby affecting decidualization with AIRE and HOXA ‐10 as the major players as well as lack of implantation site formation due to impact on angiogenesis‐associated genes. Conclusion DOCK 180 has an indispensable role in pregnancy establishment as knocking down Dock180 abrogates pregnancy by a consolidated impact on decidualization and angiogenesis by regulating AIRE nuclear entry.