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2123 Genes Regulating Implantation and Fetal Development [Frontiers in Bioscience 11, 2123-2137, September 1, 2006] Genes regulating implantation and fetal development: a focus on mouse knockout models 1 1 2 ,3 Surendra Sharma , Shaun P. Murphy , and Eytan R. Barnea 1 Departments of Pediatrics and Pathology, Women and Infants’ Hospital of Rhode Island-Brown University, Providence, RI, 2 SIEP, the Society for the Investigation of Early Pregnancy, Cherry Hill, NJ and 3 Department of Obstetrics, Gynecology and Reproductive Sciences, UMDNJ/Robert Wood Johnson Medical School, Camden, NJ TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Endogeous gene expression 3.1. Gene expression in blastocyst implantation 3.2. Gene expression (silencing) in the embryo 4. Mouse knockout models of reproductive-related genes 4.1. Cytokines 4.2. Cyclooxygenase-2 4.3. Insulin-like growth factor system 4.4. Matrix metalloproteinase system 4.5. Transcription factors involved in placental development 4.6. Indolamine-2,3-dioxygenase 5. Conclusions 6. Acknowledgements 7. References 1. ABSTRACT 2. INTRODUCTION Timely and efficient regulation of blastocyst Mammalian reproduction represents a highly implantation and fetal growth are essential for the orchestrated and intricate process. The spatial and successful reproduction of viviparous mammals. temporal regulation of a fetal-maternal crosstalk is required Disruptions in this regulation can result in a wide variety of for a successful pregnancy (1-5). After fertilization, the human gestational complications including infertility, developing blastocyst must invade and establish itself in the spontaneous abortion, fetal growth restriction, and maternal endometrium, from which it will eventually gain premature delivery. The role of several groups of factors, the crucial protection and nourishment required for including cytokines, hormones, transcription factors, extra- development throughout gestation. Successful blastocyst cellular proteinases, and angiogenic factors has been implantation is contingent on two early and independent suggested in both implantation and regulation of fetal processes. While being transported through the fallopian growth. Due to the inherent difficulties of studying tube, the embryo must undergo developmental changes, implantation and fetal development in humans, much of our which culminate in the ability to implant and become knowledge of the genes involved in these processes has invasive. In conjunction, and just as important, the uterine been derived from animal models. The critical genetic loci endometrium must undergo physiological and functional involved in blastocyst implantation and fetal growth will be changes that allow it to become receptive to the implanting discussed with a focus on those genes with available mouse blastocyst. Thus, the process of blastocyst implantation knockout models. requires the coordinated expression of a multitude of both 2123 Genetic evaluation of implantation and fetal development maternal and embryonic factors including cytokines, of a certain gene product(s) from conception is often growth factors, hormones, adhesion molecules, and accompanied by partially compensatory gene expression of prostaglandins. Disruption in the regulation of this crosstalk genes whose products have related or overlapping can result in lowered fertility due to decreased implantation functions, thus obscuring the phenotypic consequences of efficiency. Several gene products, such as interleukin-1 many gene knockouts. This appears especially true with (IL-1) and leukemia inhibitory factor (LIF) appear very respect to genes involved in implantation, placentation, and important for this process (6, 7). In addition, blastocyst fetal growth. With rare exceptions, most gene knockout implantation is likely to be influenced by embryo-regulated models currently available result in only subtle preimplantation programming which is likely to begin at a reproductive defects, which may only be apparent upon two cell embryo stage (8, 9). encounter with a second insult in the form of inflammatory signals or other stressors. Nonetheless, gene knockout After successful implantation, the major embryo- mice have provided crucial insights into the functional derived structure that regulates fetal growth is the placenta requirements of specific genes ni the genetic networks (10-13). In humans and mice, a hemochorial placenta involved in reproduction. This review will attempt to forms (14). In this type of placenta, the placental provide an overview of the dynamics of gene expression trophoblast cells are in direct contact with the maternal found in the embryonic and maternal reproductive tissues blood supply. Especially in humans, the placenta is marked involved in the processes of implantation and fetal by a deep trophoblast invasion into the maternal development and, with focus on studies of major models of endometrium. Accompanying this invasion is the lining of gene ablated laboratory mice. decidual vascular endothelial cells by invading trophoblasts. These processes establish an efficient 3. DISCUSSION maternal fetal vascular exchange, crucial to the nutrient needs of the fetus. Many diseases of the neonate and the 3.1. Gene expression in blastocyst implantation adult are thought to have their origins in the placental Initiation of successful establishment of regulation of fetal metabolism and development (15). pregnancy involves two fundamental elements, Placentation is regulated by both embryonic and maternal developmental changes in the embryo which prepare it for tissues. As in implantation, this process requires the implantation and maternal recognition of pregnancy. coordinated expression of both fetal and maternal genes. Unless those elements are assured, maternal recognition of Much progress has been made into understanding the pregnancy will not take place and implantation can not regulation of trophoblast cells differentiation, especially the succeed. The process of maternal recognition of pregnancy many transcription factors involved. In addition, various initiates shortly after fertilization and involves secretion of secreted factors are also important in promoting the specific immunomodulatory factors that allow for maternal invasion of the trophoblast into the maternal decidua. immune receptivity of pregnancy, particularly molecules Among these, the matrix metalloproteinases (MMPs), such as pre-implantation factors (PIF) (8, 9, 28). which are expressed by invading trophoblasts , disrupt the decidual extracellular matrix (16-18). Additionally, the Implantation is a dynamic process where at each tissue-inhibitors of metalloproteinases (TIMPs), which are stage multiple processes are involved, such as expressed by the decidual stroma and regulate the actions adhesiveness, invasiveness, or maternal receptivity. Models of MMPs, are particularly well studied. Angiogenic factors that could dissect each phase and identify the governing secreted by trophoblast cells as well as uterine natural elements involve would be very useful but are not currently killer (uNK) cell-derived IFN-g play an important role in available. It should be noted that even within the remodeling the maternal decidual arteries and in endometrium distinct regions can be identified- those that establishment of an efficient fetal-maternal vascular are intimately related to implantation and have different exchange (19). In addition, uNK cell-derived IFN-g has morphology and hormonal and cytokine secretion patterns been suggested to limit the invasiveness of trophoblast into than those at distant sites, as examined by endometrial the deciduas (20). To maintain a pregnancy-compatible microarray analysis (28), further illustrating the uterine milieu, IL-10, a potent anti-inflammatory cytokine significance of specific embryo derived factors. produced at the fetal-maternal interface (20-27), is Upregulation of immune-related genes IL-15Ralpha, IL15, expressed during early and through mid-gestation (27). DAF, IDO, Lpn, NKG5, IRF-1, and NKAT2 is found in Along with its variety of roles in the regulation of local secretory versus proliferative human endometrium using RT uterine immunity, IL-10 exerts a positive role in PCR in endometrial biopsies from healthy women. These trophoblast survival, and regulation of placentation genes may be involved in uNK cells proliferation blocking (Sharma S, Unpublished data). their cytolytic activity, T cell inhibition, and inhibition of the classical complement pathway (29). Differences in exp ression To complement and extend this knowledge, the patterns in human endometrium between LH+2 to LH+7 days use of gene-ablated or knockout mice has proved to be a were examined using gene arrays (30). This reveals major powerful tool furthering our understanding of gene changes especially in the expression of PP-14 (glycodelin), function. To date, a wide range of knockout mice strains (31), osteopontin (32), IGFBP-3 (33, 34), crystallin alphaB have been created, many with ablation of genes whose (35), GPx-3, claudin-4, and SLC1A1 genes. Interestingly, expression is associated with reproduction. However, a expression of 153 genes was found to be elevated compared to major concern with the interpretation of data from mouse 58 genes that showed decreased expression during the knockout models is the phenomenon of redundancy. Lack endometrial implantation window. 2124 Genetic evaluation of implantation and fetal development Differential expression of genes also occurs in These studies illustrate again that the placenta has the decidua and chorionic
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