Fertilization is an intricate dance that starts long before the two gametes actually meet. A topic of both scientists and lay peoples' fascination for several centuries following the first observations of sperm cells and oocytes, the process is still not completely understood. Each step of the fertilization process is required for the next one, yet is irreversible. Once the gametes are committed to fertilization, they either meet or die.
To further our understanding of fertilization, it is important to constantly re-examine the existing paradigms as we apply innovative instrumentation and novel genomic, proteomic, and metabolomic knowledge to these studies. Examples of how each is rapidly evolving are highlighted in the following, recent SBiRM papers: Improving Efficiencies of Locus-Specific DNA Methylation Assessment for Bovine In Vitro Produced Embryos (Ewa Wroclawska, et al. (2010) Syst Biol Reprod Med 56(1):96–105); Proteomics in the Study of the Sperm Cell Composition, Differentiation and Function (Rafael Oliva, et al. (2008) Syst Biol Reprod Med 54(1):23–36); and Freezing-Free Preservation of Human Spermatozoa – A Pilot Study (Jonathan M. Riel, et al. (2007) Syst Biol Reprod Med 53(5):275–284).
Along this line, papers published in SBiRM since its inception reveal compelling, and often surprising new discoveries concerning major fertilization mechanisms and their perturbation that have lead us on the path to new paradigms. These include: Embryonic Resorption and Polycyclic Aromatic Hydrocarbons: Putative Immune-mediated Mechanisms (Jacqui Detmar and Andrea Jurisicova (2010) Syst Biol Reprod Med 56(1):3–17); Sperm-surface ATP in Boar Spermatozoa is Required for Fertilization: Relevance to Sperm Proteasomal Function (Young-Joo Yi, et al. (2009) Syst Biol Reprod Med 55(2): 85–96); Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders (Frédéric Leduc, et al. (2008) Syst Biol Reprod Med 54(1):3–10); and Sperm Chromatin Released by Nucleases (Igor B. Nazarov, et al. (2008) Syst Biol Reprod Med 54(1):37–46).
Five review papers in this Special Issue, arranged in the natural order of fertilization events from sperm capacitation to activation/remodeling of the zygotic genome and blastocyst formation, discuss fertilization in light of these recent discoveries. Following gametogenesis and maturation, spermatozoa and oocytes have to find their way through the female reproductive system. While the oocyte descends directly to the fertilization site, the spermatozoa have to slow down transiently as they bind to the epithelium of oviductal sperm reservoir, awaiting capacitation and hyperactivation, induced by paracrine signals triggered by ovulation. Substantial progress has been made in recent years in the understanding of signaling pathways that operate during sperm capacitation, which is the topic of our first review, Factors Regulating Sperm Capacitation, by Janice Bailey.
Following sperm egg recognition, the fertilizing mammalian spermatozoon penetrates the outer egg vestments and contacts the egg coat, zona pellucida. Zona function and the mechanism of sperm-zona binding and penetration has been studied in great detail for over 100 years, with major advances made in the last 30 years through unraveling of the molecular composition of zona pelluicida and characterization of the sperm receptor glycoproteins(s). While the prevailing view is that spermatozoa bind to branched oligosaccharides that decorate the ZP proteins, alternative interpretations have emerged in response to the complexity of glycans found on ZP proteins and the paucity of detailed glycobiological studies of the ZP matrix. This long-overdue work is now being pursued by glycobiologists like Gary Clark who provides an update on the fruit of these efforts, including a new ‘domain specific model’ of sperm-zona binding in The Mammalian Zona Pellucida: A Matrix That Mediates Both Gamete Binding and Immune Recognition?
Once the fertilizing spermatozoon passes through the zona, it reaches the perivitelline space and adheres to the oocyte plasma membrane, the oolemma. Subsequent to sperm-oolemma fusion, the perinuclear skeleton of the sperm head dissolves in the ooplasm and releases the soluble cytosolic factors once christened ‘SOAF’, for the sperm borne-oocyte activating factors. While the SOAF hypothesis of oocyte activation has been elaborated, an older, alternative, or in hindsight perhaps synergistic mechanism of receptor-binding induced oocyte activation has been overlooked. Some remember a study by Maleszewski, Kimura, and Yanagimachi (1996; Sperm membrane incorporation into oolemma contributes to the oolemma block to sperm penetration: evidence based on intracytoplasmic sperm injection experiments in the mouse. Mol Reprod Dev 44(2):256–259), suggesting that the membrane-receptor mediated events of sperm-ollema adhesion may in the end be important for oocyte activation, as in their absence, the murine zygotes fertilized by intracytoplasmic sperm injection (ICSI) fail to establish an adequate anti-polyspermy defense. Work from several laboratories, including that of contributors Kenneth White et al., show that coincubation of oocytes with peptides mimicking the oolemma integrin-binding, disintegrin domain of sperm plasma membrane proteins from the ADAM family, induces some events of oocyte activation, most notably the initial calcium transient in the ooplasm and formation of the female pronucleus. This review, Oolemma Receptors and Oocyte Activation, will shed light on why it may be so and how the oocyte intergin-sperm disintegrin interaction may act in synergy with soluble, sperm-released cytosolic factors during fertilization.
Speaking of ICSI, the failure to mobilize oocyte's anti-polyspermy defense may not be the sole shortcoming of this undisputed revolutionary ART technique. As Gianpiero Palermo and colleagues explain in their review, What To Do When ICSI Fails? many events of fertilization by ICSI differ from natural fertilization during which the spermatozoon penetrates the egg vestments and fuses with oolemma on its own. Besides an alternative and sometimes failure-prone activation mechanism, the list includes the introduction of a more or less intact acrosome in the ooplasm, delayed sperm nucleus decondensation, and possibly delayed or aberrant re-setting of epigenetic marks carried by the male genome.
It is thus no surprise that epigenetic defects are increasingly being discussed in connection to ICSI and other ART techniques. A hot new research area such as epigenetics warrants a contribution from a relative newcomer with a fresh perspective; Rocio Rivera, Epigenetic Aspects of Fertilization and Preimplantation Development in Mammals: Lessons from the Mouse, gives us a concise overview of mechanisms by which epigenetic marks are established during gametogenesis, erased shortly after fertilization, and reestablished during preimplantation embryo development. This paper completes the group of reviews that follows the natural cascade of fertilization events from sperm capacitation to zygotic development.
We present this Special Issue with the goal of stimulating out of the box thinking in fertilization biology. We hope that this sample of new thinking from a relatively new journal will be useful to all students of fertilization, regardless of their specialty and stage of career.
Peter Sutovsky, Ph.D.
Special Issue: Focus on Fertilization
Guest Editor, Systems Biology in Reproductive Medicine