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Mammalian fertilization comprises sperm migration through the female reproductive tract, biochemical and morphological changes to sperm, and sperm-egg interaction in the oviduct. Recent gene knockout approaches in mice have revealed that many factors previously considered important for fertilization are largely dispensable, or if they are essential, they have an unexpected function. These results indicate that what has been observed in in vitro fertilization (IVF) differs significantly from what occurs during "physiological" fertilization. This Review focuses on the advantages of studying fertilization using gene-manipulated animals and highlights an emerging molecular mechanism of mammalian fertilization.
Introduction
In the early 1950s, Min Chueh Chang and Colin Russell Austin independently found that mammalian sperm must spend some time in the female reproductive tract before they acquire the ability to fertilize eggs (1, 2). The phenomenon underlying the acquisition of fertilization capability is called sperm capacitation (3), and the discovery of Chang and Austin made it possible to perform mammalian fertilization in vitro by mixing capacitated sperm with ovulated eggs, a procedure used by in vitro fertilization (IVF) clinics today (4) (Figure 1). This simplified in vitro experimental system (5) also allowed researchers to intensively study rhe mechanism of fertilization. Indeed, using this system together with biochemical approaches, such as competitive binding of antibodies and ligands that interact with sperm, eggs, and their surroundings, various factors were reported to be important for mammalian fertilization.
The development of gene-knockout technology (6, 7) has allowed researchers to test in vivo the findings from IVF studies. Numerous factors considered to be key molecules have been examined for their importance during fertilization (Tables 1 and 2). Surprisingly, these experiments revealed that many ofthe sperm factors thought to be important for fertilization, including the acrosomal protease acrosin (Acr) (8), the zona pellucida (ZP) binding protein ß- 1,4-galactosyl transferase 1 (B4galtl) (9, 10), and the egg fusion protein fertilin (a heterodimer that consists of two subunits, a disintegrin and metallopeptidase domain lb [Adam lb] and Adam2) (11), were not essential. It can be argued that in vivo, compensatory mechanisms supplant the function ofthe gene targeted in a knockout mouse. However, these factors were identified as important for fertilization in studies using antibodies that blocked IVF by targeting a single epitope of these factors, and no...