Overview of Fertilization Research

Fertilization is the union of two gamete cells; egg and sperm that combines two paternally prepared genetic materials and that gives rise to a newborn with a distinct genetic background to their parents. Although recent advances in biotechnology (i.e. somatic cell nuclear transfer) has enabled us to create cloned animals in some species including mammals, whose genetic materials are practically as same as their donor animals, there has been no exception in that fertilization is the only mean for natural offspring in sexual reproduction system.  Therefore, the understanding the molecular and cellular mechanisms of fertilization has been a long-thought theme in biology and medicine, by which we may establish more effective strategies for medical and pharmaceutical treatments, for agricultural and industrial productions, for taking care of environmental issues, and most of all, for understanding of ourselves, the human being.  Fertilization, by its terminology, cover several successive aspects of reproduction; including gametogenesis (oogenesis/spermatogenesis and acquisition of ability to be fertilized), gamete interaction with reproductive tract (especially in mammals) and with each other, gamete fusion, activation of egg/oocytes, and establishment and initiation of zygotic development (including implantation in mammals).  Practically, however, the research field of fertilization covers more deeply inside from the sperm-egg interaction through the initiation of development than other processes.  In this view, the following three questions have been asked as general and major questions in the fertilization field. How does sperm (or egg) recognize and interact with egg (or sperm)? How do sperm and eggs fuse with each other?  How does fertilized egg get activated to initiate embryonic development?

How do Sperm and Egg Interact and Fuse with Each Other?

A number of studies have been conducted to answer aforementioned questions by using several model organisms. Not only vertebrates like mammals, birds, reptiles, amphibian, and fishes, but also invertebrates such as insects, nematodes, and sea creatures have been employed.  A table shown below depicts current state of our knowledge on a sequence of events associated with fertilization, in other words, signal transduction of fertilization, by highlighting four organisms analyzed extensively; sea urchin, frog, newt, and mouse.

At present, sperm-egg interaction at the plasma membrane level is most uncertain subject. Biochemical and immunochemical studies in the mouse have identified some candidates for sperm-egg membrane interaction; for instance, a disintegrin and metalloproteinase or ADAMs in sperm and integrins in eggs. However, genetic deletion of these molecules by gene knockout could not eliminate the ability of eggs or sperm to undergo membrane interaction, indicating that these molecules are not essential for this process. Until now, no gene knockout experiments have succeeded in obtaining phenotype that sperm-egg interaction is impaired. On the other hand, the same experimental approach has identified two gene products, egg CD9 and sperm Izumo, as essential components for sperm-egg membrane fusion in mouse. CD9 is a member of tetraspanin molecules that contain four transmembrane domains as well as two extracellular loops and two cytoplasmic sequences. It is also known that CD9 constitutes a protein complex with certain kinds of integrin, a cell adhesion protein, and serves as membrane organizer. Recent reports have demonstrated that fragments of egg membranes containing CD9 are transferred to sperm surface, by which sperm may acquire the ability to fertilize egg. It should also be noted that sperm surface also express functional integrin complexes that seem to be important for sperm-egg interaction and fusion. Izumo 1 processes an immunoglobulin-like domain in its extracellular sequence, which has been implicated in molecular interaction in several other immunoglobulin-like domain-containing proteins. Both CD9 and Izumo 1 proteins, however, do not possess intrinsic activity for membrane fusion like SNARE complex. Therefore, it seems that these two proteins act to orchestrates structural assembly and/or function of membrane-associated molecules directly involved in fusion process. (to be continued)

Research Background and problems on Cancer Cell Project

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