Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation

Abstract

Uterine decidualization, characterized by stromal cell proliferation, and differentiation into specialized type of cells (decidual cells) with polyploidy, during implantation is critical to the pregnancy establishment in mice. The mechanisms by which the cell cycle events govern these processes are poorly understood. The cell cycle is tightly regulated at two particular checkpoints, G1-S and G2-M phases. Normal operation of these phases involves a complex interplay of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors (CKIs). We previously observed that upregulation of uterine cyclin D3 at the implantation site is tightly associated with decidualization in mice. To better understand the role of cyclin D3 in this process, we examined cell-specific expression and associated interactions of several cell cycle regulators (cyclins, cdks and CKIs) specific to different phases of the cell cycle during decidualization in mice. Among the various cell cycle molecules examined, coordinate expression and functional association of cyclin D3 with cdk4 suggest a role for proliferation and, that of cyclin D3 with p21 and cdk6 is consistent with the development of polyploidy during stromal cell decidualization.

Determinants of uterine aging: lessons from rodent models

“…This extensive cell proliferation and polyploidy event occurs in a well-organized manner. It firstly takes place at the antimesometrial side around the embryo on day 6, which is defined as primary decidual zone (PDZ) and then extends to the stromal cells next to the PDZ forming a fully developed zone around the PDZ, termed the secondary decidual zone (SDZ) [27]. This living embryo induced decidualization can also be mimicked by the application of artificial stimuli to a receptive pseudopregnant uterus, or one that has been appropriately primed by ovarian steroids, though not totally identical [28].…”

Cell cycle regulatory control for uterine stromal cell decidualization in implantation

“…The development of decidua or deciduoma in rodents is associated with the formation of multinucleate and giant cells (Sachs & Shelesnyak 1955, Ansell et al 1974, Moulton 1979, Tan et al 2002. The polyploid decidual cells are terminally differentiated cells and are shown to be developed through a unique process requiring transition from the mitotic cell cycle to an endoreduplication cycle (endocycle), in which cells undergo a repeated round of DNA replication without successive cell division (cytokinesis).…”

“…An altered cell cycle regulation has been considered to be associated with the development of cellular polyploidy. In mice, the development of decidual cell polyploidy leads to the generation of large mono-or binucleated cells, consisting of DNA with four, eight, and even higher multiples of the haploid complement (Sachs & Shelesnyak 1955, Ansell et al 1974, Moulton 1979, Tan et al 2002. Previous studies have shown that the antimesometrial decidualizing stroma is comprised of two populations of cells: first one that divides fast before undergoing differentiation and the second one that undergoes differentiation without further division, thus leading to the development of cellular heterogeneity in the decidual bed (Moulton 1979, Tan et al 2002.…”

“…In the receptive uterus on day 4 of pregnancy, cyclin D3 is very weakly detected only in the stromal cells; however, this gene expression is remarkably induced in the decidualizing stroma either at the site of implantation or in artificially induced decidualization . Based on multiple approaches, viz., expression studies for various cell cycle regulators, functional assays for CDKs activity and analysis of cell cycle phase-specific distribution of decidual cells have strongly positioned us to suggest that cyclin D3 is associated with stromal cell proliferation, differentiation, and polyploidy events during decidualization (Tan et al 2002). Coordinate expression of CDK4 and cyclin D3 at the site of implantation in stromal cells on day 5 has suggested that these regulators play roles in cellular proliferation with the onset of implantation.…”

“…By contrast, the expression of cyclin D3, but not the CDK4, at the antimesometrial decidual bed (within the SDZ) is further stimulated. Furthermore, in the SDZ, the persistent expression of CDKN1A and a new expression for CDK6 in conjunction with cyclin D3 forming a ternary complex appears to direct the development of decidual cell polyploidy (Tan et al 2002). The presence of cyclin E, cyclin A, and CDK2 with concomitant downregulation of cyclin B and CDC2A in polyploid decidual cells supports the view that these cells are undergoing an incomplete cycle (or endocycle) pathway by inducing an arrest prior to the G 2 -M phase transition (Tan et al 2002).…”