Mouse models of implantation

The process of implantation, necessary for nearly all viviparous birth, consists of tightly regulated reactions including apposition of the blastocyst, attachment to the uterine epithelium and decidualization of the uterine stroma. In order for implantation to be successful, a reciprocal interaction between an implantation competent blastocyst and receptive uterus must be achieved. A more thorough understanding of the molecular mechanisms that regulate uterine receptivity and implantation is of clinical relevance to correct implantation failure and improve pregnancy rates. As molecular methodologies have evolved in recent times, the use of in vivo models to elucidate the molecular mechanisms involved in implantation has increased. The mouse has emerged as a powerful model to investigate implantation owing to the ability to control uterine physiology through exogenous stimuli, and more recently, the ability to manipulate gene expression. This review describes the evolution of the mouse as a model for understanding uterine implantation, including exciting new advances in this field, and describes a novel genetic pathway that can be elucidated from these models.

Introduction

Human infertility is a global problem with social and economic impact. According to the 2002 National Survey of Family Growth conducted by the Centers for Disease Control and Prevention, 10% of women in the United States have had an infertility-related medical visit, and an additional 7% of married couples of reproductive age have difficulty conceiving [1]. Although great strides have been made in assisted reproductive technology, especially in in vitro fertilization and embryo manipulation, the goal of successful implantation remains elusive. A great number of these failures are probably caused by the transfer of embryos into a nonreceptive uterus. Therefore, the elucidation of the complex progression of molecular and physiological events that comprise implantation is of utmost importance. This review focuses on how mouse models have facilitated our understanding of uterine implantation and preimplantation uterine events that render the uterus receptive to the blastocyst. Revisiting this field is timely owing to the recent developments in our ability to conditionally ablate genes in the mouse uterus.

Implantation has long been known to be a steroid hormone dependent process. Coordinated action of both estrogen (E2) and progesterone (P4) are necessary for the preparation and process of implantation into the mouse endometrium. During normal mouse pregnancy, an E2 surge on day (d)1 (d1 = vaginal plug) stimulates uterine epithelial cell proliferation. A decrease in E2 levels on d2 leads to apoptosis of a large number of epithelial cells. P4, from the newly formed corpora lutea on d3, initiates uterine stromal cell proliferation. In conjunction with the high P4, an acute E2 spike on d4 further stimulates uterine stromal proliferation and renders the uterus receptive for the blastocyst to implant (as reviewed in [2]). In mice, the process of implantation consists of apposition between the trophectoderm layer of the blastocyst with the luminal epithelium, attachment of these layers and, finally, invasion of the uterine luminal epithelium by the embryo. Upon embryo invasion, the uterine stromal cell is rapidly remodeled in the process of decidualization (as reviewed in [3]). Decidualization is characterized by morphological and functional changes in the uterine stromal cells in the form of endometrial stroma proliferation and differentiation into large epitheliod decidual cells. Decidualization is critical for establishment of a fetal–maternal interface during implantation and remains dependent upon continued P4. The mouse models discussed in this review have contributed to the physiological and molecular understanding of this process.