TGFβ superfamily signaling and uterine decidualization

Abstract

Decidualization is an intricate biological process where extensive morphological, functional, and genetic changes take place in endometrial stromal cells to support the development of an implanting blastocyst. Deficiencies in decidualization are associated with pregnancy complications and reproductive diseases. Decidualization is coordinately regulated by steroid hormones, growth factors, and molecular and epigenetic mechanisms. Transforming growth factor β (TGFβ) superfamily signaling regulates multifaceted reproductive processes. However, the role of TGFβ signaling in uterine decidualization is poorly understood. Recent studies using the Cre-LoxP strategy have shed new light on the critical role of TGFβ signaling machinery in uterine decidualization. Herein, we focus on reviewing exciting findings from studies using both mouse genetics and in vitro cultured human endometrial stromal cells. We also delve into emerging mechanisms that underlie decidualization, such as non-coding RNAs and epigenetic modifications. We envision that future studies aimed at defining the interrelationship among TGFβ signaling circuitries and their potential interactions with epigenetic modifications/non-coding RNAs during uterine decidualization will open new avenues to treat pregnancy complications associated with decidualization deficiencies.

Keywords: Activin; BMP; Decidualization; SMAD; TGF-beta; TGFBR1.

Fig. 1

Schematic illustration of TGFβ superfamily signaling and its involvement in decidualization. a A diagram of TGFβ superfamily signaling. TGFβ superfamily ligands (e.g., TGFβs, activins, and BMPs) induce the formation of membrane-associated receptor complexes comprising type 1 and type 2 receptors. Activated receptor machinery phosphorylates SMAD proteins (i.e., SMAD2/3 and SMAD1/5/9), which cooperate with SMAD4 to function in a canonical pathway. The non-canonical pathways generally include, but are not limited to, ERK1/2, JNK, P38, and PI3K/AKT, the activation of which is SMAD-independent. b TGFβ signaling components and uterine decidualization. Experimental evidence, particularly those from genetically modified mouse models, has revealed critical functions of various TGFβ signaling elements in the process of uterine decidualization. Disruption of BMP2, ACVR1, BMPR1A, BMPR2, SMAD1/5/4, SMAD3, or FST leads to defects in uterine decidualization. In contrast, LEFTY seems to be a suppressor of uterine decidualization. Further clarification of the function of TGFβ superfamily ligands (e.g., TGFβs and activins) and the usage of type 1 and type 2 receptors by different signaling molecules is warranted. Studies are also needed to assess the role of the non-canonical TGFβ signaling branch in decidualization and potential interactions between TGFβ superfamily signaling and epigenetic modifications and microRNAs in this key remodeling event. As decidualization is a highly orchestrated process regulated by hormonal, cellular, and molecular mechanisms, this diagram focuses on highlighting molecules associated with the TGFβ signaling pathway