Prostaglandin E2 and Progesterone Receptor Coordinately Regulate Primary Cilia for Proper Decidualization

Abstract

Decidualization, the process by which endometrial stromal cells differentiate into decidual cells in response to prostaglandin E2 (PGE2) and progesterone receptor (PGR) signaling, is essential for proper implantation and placentation. Primary cilia, microtubule-based cellular antennae, contribute to various differentiation processes, including decidualization. In this study, we demonstrated that both the proportion of ciliated cells and ciliary length increased in a time-dependent manner during in vitro decidualization. In a mouse model, after copulation, the proportion of ciliated cells fluctuated, but ciliary length progressively increased over time. Additionally, we observed defective primary cilia in the endometrium of women with recurrent miscarriages. Mechanistically, we found that primary cilia were present before the expression of decidual markers under decidual stimulation. Depletion or inhibition of primary cilia impaired decidualization, highlighting their critical role in this process. Furthermore, we identified the PGE2-PKA-CREB1 axis as a key regulator of ciliary growth and PGR upregulation. Upon progesterone stimulation, active PGR further increased ciliary length, thereby facilitating decidualization. Thus, our study not only establishes a link between ciliary length and decidualization but also elucidates the sequential regulation of ciliary dynamics by PGE2 and PGR in a coordinated manner.

Keywords: cAMP; decidualization; primary cilium; progesterone receptor; prostaglandin E2.