CDC42 governs normal oviduct multiciliogenesis through activating AKT to ensure timely embryo transport

Abstract

Ciliated and secretory cells are two major cell types that comprise the oviduct epithelia. Accumulating evidences support a role of oviductal multiciliated epithelia for embryo transport, however the mechanisms underlying this specialized cell type differentiation remain elusive. Here, we report that CDC42 depletion in oviduct epithelia hampers the morphogenesis of multiciliated cell, and results in embryo retention, leading to early pregnancy failure. Utilizing the oviduct organoid model, we further observed that CDC42 guides secretory cells transition into multiciliated cells independent of its GTPase activity and the well-known Notch pathway. Further exploration uncovered the AKT as a novel indispensable regulator for multiciliated cells differentiation, whose activity was maintained by CDC42 through interacting with the p110β. Consistently, re-activating AKT partially incites multiciliated cells differentiation in Cdc42 knockout oviductal organoids. Finally, low levels of CDC42 and phospho-AKT with reduced multiciliated cells in the oviduct are observed in women with ectopic pregnancy. Collectively, we provide previously unappreciated evidence that CDC42-AKT signaling is a critical determinant for morphogenesis of oviduct multiciliated cell, which possesses the clinical application in understanding the pathology of ectopic pregnancy and facilitating the development of prevention strategies.

Integrative Proteomics and Transcriptomics Profiles of the Oviduct Reveal the Prolificacy-Related Candidate Biomarkers of Goats (Capra hircus) in Estrous Periods

“…Intraflagellar transporter protein 140 (IFT140) is a member of the intraflagellar transport (IFT) protein family and is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. Ciliated and secretory cells are the two main cell types that constitute the oviductal epithelium [ 47 ], whereas embryo transport is realized by the complex interaction of smooth muscle contraction, cilia beat, and fluid flow in the oviduct [ 47 , 48 ]. Therefore, IFT140 might display a key role in maintaining the activity of the oviduct cilia.…”

Precision-engineered biomimetics: the human fallopian tube

“…There are slight architectural and cellular differences between the different regions of the fallopian tube. The percentage of epithelial cells at the fimbriated end that are ciliated, for example, is higher than throughout the ampulla [45][46][47] . However, the general mucosal folding architecture, ECM arrangement and epithelial/stromal cell types are preserved.…”

The autophagy protein, ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy

“…Any perturbations in these early pregnancy events can lead to adverse ripple effects that can compromise pregnancy outcomes. Previous studies have reported that impaired oviductal transport of embryos can lead to pregnancy failure and cause infertility in mice [3][4][5][6]. However, the underlying mechanism is not yet completely understood.…”