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THE SAGA OF A MALE FERTILITY PROTEIN (SP22)
Klinefelter, G R. AND J. E. Welch. THE SAGA OF A MALE FERTILITY PROTEIN (SP22). ANNUAL REVIEW OF BIOMEDICAL SCIENCES 1:145-184, (1999).
To report on the progess with development of a novel sperm protein (SP22) that is well correlated with the fertility of matured sperm
Toxicologic studies designed to identify chemical-induced alterations in the structure and function of the epididymis, particularly the acquisition of fertility by proximal cauda epididymal sperm, have lead to the discovery of a novel sperm protein (SP22) that is well correlated with the fertility of these 'matured" sperm. SP22 is the first sperm-associated fertility protein identified following toxicologic investigation; a convincing demonstration that toxicology can be a tool to understanding fundamental physiology. SP22 is completely novel to reproductive biology, and has only recently been described (i.e. DJ-1 /RS) in somatic tissues. The presence of a unique mRNA transcript in the testis, that appears around the time of round spermatid formation, together with the immunolocalization of SP22 on rete sperm, argue that SP22 is differentially regulated and expressed on maturing sperm in the testis following meiosis. With the generation of multiple antibodies to SP22 (i.e. peptide, recombinant) there is increasing evidence that the sperm-associated form of SP22 is expressed on the equatorial segment in rats, bulls, and humans. Since the addition of antibody to SP22 inhibits fertilization both in vitro and in vivo, it is tempting to speculate that SP22 is pivotal to initial sperm-egg binding. Unfortunately, as no function has been definitely established for the ubiquitously expressed somatic form, it is difficult to imagine what molecular role SP22 may play on the sperm membrane. While denatured, SP22 is one of several isoelectric variants at 28 kD, purification of native SP22 indicates a molecular weight maximum of approximately 450 kD. Thus, it appears that SP22 represents a single, charged molecule in a family of charged variants of identical molecular weight which collectively contribute to a multimeric complex. Presumably the expression of SP22 on a population of sperm as it relates to their fertility represents the relative percentage of SP22 (the pI 5.2.28 kD variant) within this 450 kD complex. If so, the "function" of SP22 may well be defined by the function of the 450 kD membrane complex in the sperm membrane. The percentage of SP22 may contribute to the overall size of the multimeric complex, which in turn determines the degree to which the complex functions. By analogy it is well known that the activity of many enzymes (e.g. catalase, NADP-dependent malate dehydrogenase, formyltransferase) increases as the protein transitions to higher multimeric states (e.g. dimer to tetramer; Shimna, S. et al., 1998; Iglesias, A., 1990). While difficult and time-consuming, understanding the biological role of native SP22 on the sperm membrane is crucial to designing and using SP22, and/or target specific probes (i.e. nonprotein small molecules, recombinants, monoclonal antibodies ), that might act as agonists or antagonists, and serve as potential therapeutic enhancers or contraceptives, respectively. As additional antibodies are generated to SP22 (i.e. monoclonals to SP22 recombinants, monoclonals to the native SP22 multimeric complex) we will begin to characterize the ontogeny of this protein in the testis, as well as its physiological regulation in the testis and epididymis. It is important to determine in which stage(s) of spermatogenesis the germ cell specific SP22 transcript is expressed, which germ cells express it, the cellular localization within these cells, and if germ cell expression is hormonally regulated. Moreover, it is important to understand how SP22 expression is regulated (i.e. stabilized and/or modified) during epididymal transit. For example, it remains to be determined whether the change in pattern of immunolocalization observed for rete sperm and cauda sperm represents loss from one region and subsequent acquisition in another region, a transmembrane relocalization, or a masking and unmasking phenomenon. Only with this information will it be possible to determine SP22's potential as biomarker of toxicity in the adult testis and epididymis, as well as in the developing male reproductive tract. Finally, realizing the complete potential for SP22 as a biomarker of toxicity, as a fertility diagnostic, a therapeutic enhancer, or as a contraceptive, will be possible only once species differences and similarities, particularly with regard to ontogeny, regulation, and molecular function are known and understood.