MOLECULAR MEDICAL APPROACHES FOR ALLEVIATING INFERTILITY AND UNDERSTANDING ASSISTED REPRODUCTIVE TECHNOLOGIES

Fertilization is a precisely orchestrated cascade of events that resul ts in the union of paternal and maternal genomes and in the establishm ent of mitotic potential of the zygote. To initiate embryonic developm ent, the structures of the fertilizing sperm have to be disassembled a nd transformed into zygotic components by interactions with the cytopl asm of the egg. These interactions include the decondensation of the s perm nucleus into male pronucleus, the assembly of the zygotic centros ome, and the gathering of centrosomal proteins and sperm aster microtu bules around the sperm centriole. Both the formation of the male pronu cleus and the assembly of the zygotic centrosome are crucial steps req uired for pronuclear apposition and genomic union. The discovery of pr eviously undetected fertilization failures that are due to defects in the assembly of the zygotic centrosome, abnormal pronuclear developmen t, and compromised cytoskeletal dynamics enforces the development of n ew diagnostic strategies. Moreover, the introduction of new methods of infertility treatments, such as intracytoplasmic sperm injection and round spermatid nucleus injection into assisted human reproductive tec hnology programs, emphasizes our lack of understanding of the cellular and molecular basis of human fertilization and evokes the need for ad ditional experimentation. These efforts, however, are compromised by t he sensitive nature of human embryo research and thus are severely res tricted. Animal models that are reliable and cost-effective and that f eature the characteristics of human fertilization have therefore been sought. Rodents such as the rat, mouse, and hamster are poor models ow ing to their maternal inheritance of the zygotic centrosome that is in strong contrast with the biparentally contributed assembly of the hum an zygotic centrosome during fertilization. Although rabbits are simil ar to humans from the standpoint of mitotic potential inheritance, inf ormation on postfertilization events in rabbits are lacking. Nonhuman primates represented by the rhesus monkey proved to be a reliable mode l for human in vitro fertilization and intracytoplasmic sperm injectio n, an advantage that is further emphasized by phyllogenetic similarity . In situations in which the high cost of primate research does not al low for large-scale experimentation (i.e., when large numbers of oocyt es and embryos are needed), ruminants would be an ideal solution. Repr esented by the cow and sheep, domestic ruminants feature a fertilizati on strategy similar to that of the human. In addition, large numbers o f gametes can be obtained wherever farms and slaughterhouses are acces sible. Moreover, the detailed information on ruminant fertilization is strengthened by years of research and well-defined reproductive techn ology aimed at increasing the productivity of farm animals. Ruminants and rhesus monkeys have been extensively studied, and the data from th ese studies have been extrapolated in order to propose new strategies for the diagnosis and treatment of human infertility.