Editorial Commentary
http://www.100md.com
《男科医学杂志》
Weill Medical College of Cornell University
Hermo L, Adamali HI, Trasler JM. Postnatal development and regulation of ?-hexosaminidase in epithelial cells of the rat epididymis. J Androl. 2004 ;25:69-81.
In the present issue, Hermo et al illustrate in an elegant way for the rat epididymis the postnatal development of ?-hexosaminidase activity localized to epithelial lysosomes and the effects of orchiectomy and efferent duct ligation on its expression in different regions and in different cell types. This most recent study of epididymal ?-hexosaminidase is one of a series in which classic techniques of cell biology are used in attempts to better define the character of the epididymal epithelium. However, an earlier paper from these authors (Trasler et al, 1998) showed that some young male mice lacking the ?-hexosaminidase gene develop some epididymal abnormalities but do remain fertile. This should give us pause, perhaps, to reflect briefly on current epididymal research—how can this best be approached, and what should be its priorities? Can random studies, whether involving gene expression or histochemistry, lead us in the foreseeable future to an understanding of the key molecular events of sperm maturation or the maintenance of sperm viability (storage) in the epididymis and, perhaps, to an ability to manipulate these functions—the main issues that would seem to justify its pursuit?
In addition to studies of the epithelium of the epididymis, microsampling of different regions has shown much about its changing ionic profile and about a variety of components that include many proteins, in particular, as well as glycoprotein modifying enzymes, glycerol-phosphocholine, inositol, carnitine, and others (Brooks, 1990). At the same time, investigation during the past 4 decades has provided a fertility profile for the epididymis in a few mammalian species and has detected several changes in the sperm cell that seem linked to its fertilizing ability: the cross-linking of protein-bound thiols, the change in the form of the acrosome and/or the character of its content, and, observed 90 years ago, the onset of the capacity for progressive motility that is related in part to certain metabolic enzymes of the sperm tail but probably also to change(s) in its plasmalemma. Some facets of the maturation process can occur independently of others. For example, rabbit spermatozoa withheld in the upper epididymis can for a limited period express the potential for prolonged optimal motility yet lack the ability to bind to the zona in the fallopian tube. Similarly, structural cross-linking of sperm thiols occurs readily in nonspecific conditions in vitro.
Despite this background information, it remains difficult to assign a specific function to most molecules in epididymal secretions. With the possible exception of the physical constraints brought by "immobilin" in some murid rodents at least, it has proven difficult to connect any single luminal factor to the cauda's ability to prolong the viability of mature spermatozoa. The evidence with regard to fertilizing ability does give a sense that the final key to this lies in certain changes that occur in the sperm plasmalemma. Nonetheless, the multifaceted nature of maturation brings into question whether a single component of the environment could be responsible, as a final "switch on," so to speak. Among the few examples of particular molecules that do seem to relate to the events of fertilization, a cysteine-rich secretory protein (CRISP) elaborated by and acquired in the caput appears to participate in gamete fusion (Ellerman et al, 2002), though it remains to be seen whether this is an essential factor—whether spermatozoa from males lacking its gene are unable to fertilize. In the hamster (and human?), a secretory caput glycoprotein (P26h) that associates with the periacrosomal surface appears to be a key ligand for the zona pellucida (Sullivan, 1999); in the mouse also, a protein (SED1) secreted by caput principle (sic) cells is reported to mediate initial binding to the zona (Ensslin and Shur, 2003). However, spermatozoa from some mice lacking the gene for SED1 can fertilize, in contrast to the complete inability of immature caput or noncapacitated populations, for example. This again raises the possibility discussed by Castle (2002) of some redundancy with regard to zona-binding elements on the sperm surface.
Among the difficulties involved in identifying the key features of sperm maturation and storage at a molecular level is the subtle but real problem of the present need to frame questions about many aspects of mammalian gamete function within something of a conceptual vacuum. On the basis of the little that is known about the Wolffian duct in other vertebrates, the evidence points to a leap in the complexity of its role(s) during the evolution of therian mammals. However, it is still far from clear why the final maturation of mammalian spermatozoa should involve a greater variety of posttesticular cellular changes and why at least some of these depend acutely on the environment created in the epididymis. It is equally difficult to understand what has driven the evolution of a specialized system of sperm storage in the cauda that is closely regulated by testicular androgen and usually by a lower-than-body temperature—but only in the mammalian line—with possible implications, in turn, for sperm capacitation and for evolution of the scrotum (Bedford, in press).
Such a lack of basic understanding about the state of this duct system makes it more difficult to ask the right questions and interpret results. Indeed, much epididymal research seems to exemplify the dictum of the molecular biologist Sydney Brenner, who argues that the great challenge in biology today is the turning of data into understanding as to function. While emphasis should perhaps be given as far as possible to the linking of research on the epididymis more directly to its functions, other difficulties present themselves in trying to understand the role of particular components in its fluids. Not only does sampling and analysis of the upper levels of the epididymis require special expertise, but the precise nature of the changes that spermatozoa undergo there can vary from species to species. For example, the cholesterol-phospholipid ratio in the sperm plasmalemma appears to increase during epididymal transit in the ram and goat, remains constant in the boar, and decreases in the rat and stallion (Cross, 1998). This suggests that a functional end point can be arrived at through different molecular means. At the same time, it can be a problem to interpret function even in a general way. For instance, it has been unclear in many cases whether a particular change in the sperm plasmalemma or a particular component of the environment might relate to the maturation of spermatozoa or, alternatively, to the maintenance of their viability. A focus on the developing ability to fertilize has created a tendency to think of the epididymis and its milieu primarily in terms of sperm maturation. However, it is very probable that major elements of the change(s) that the plasmalemma of the spermatozoon undergoes in the epididymis relate to its viability in the cauda and that much of the length of the duct could be devoted to preparation for maintaining that, rather than its maturation. For instance, some sperm membrane components first expressed in the mid-region of the epididymis constitute receptors for surface proteins acquired later as spermatozoa reach the cauda (HIS protein, Rifkin and Olson, 1985; CD52, Yeung et al, 1997). Furthermore, although the latter proteins were first thought to relate to sperm maturation, in the rat, rabbit, dog, and sheep at least, their expression and binding to a generally mature population first in the upper cauda suggest a tie to the events of storage.
Finally, among the models that might help us probe some of these questions, one that may be worth exploring further is the cryptepididymal male. In murid rodents and the rabbit, at least, the epididymis can be reflected to the abdomen, leaving a normal testis in the scrotum. This reconfiguration of the epididymis provides an experimental situation in which sperm maturation continues normally but in which the storage function is immediately suppressed. Deep body temperature does not seem to significantly affect the ultrastructure of the cauda epithelium, but it has easily discernible effects on fluid and ion transport across it, on the ionic and macromolecular composition of its luminal secretion, and even on gene expression in a limited way. It is possible that, perhaps together with some modulation of androgen levels, this model may provide a situation in which to probe the elements that are critical for the viability/storage of epididymal spermatozoa as distinct from those involved in their maturation.
References
Bedford JM. Enigmas of mammalian gamete form and function. Biol Rev. In press.
Brooks DE. Biochemistry of the male accessory glands. In: Lamming GE, ed. Marshall's Physiology of Reproduction. Vol 2 . London: Churchill Livingstone; 1990:569-690.
Castle PE. Could multiple low-affinity bonds mediate primary sperm-zona pellucida binding? Reproduction. 2002; 124:29-32.
Cross N. Role of cholesterol in sperm capacitation. Biol Reprod. 1998;59:7-11.
Ellerman DA, Da Ros VG, Cohen DJ, Busso D, Morgenfeld MM, Cuasnicu PS. Expression and structure function analysis of de, a sperm cysteine-rich protein that mediates gamete fusion. Biol Reprod. 2002; 67:1225-1231.
Ensslin MA, Shur BD. Identification of mouse sperm SED 1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell. 2003;114:405-417.
Rifkin JM, Olson GE. Characterization of maturation-dependent extrinsic proteins of the rat sperm surface. J Cell Biol. 1985;100:1582-1591.
Sullivan R. Interaction between sperm and epididymal secretory protein. In: Gagnon C, ed. The Male Gamete—From Basic Science to Clinical Applications. Vienna, Ill: Cache River Press; 1999 : 93-104.
Trasler JM, Saberi F, Somani IH, et al. Characterization of the testis and epididymis in mouse models of human Tay Sachs and Sandhoff diseases and partial determination of accumulated gangliosides. Endocrinology. 1998; 139:3280-3288.
Yeung CH, Schroter S, Wagenfeld A, et al. Interaction of human epididymal protein CD52 (HE5) with epididymal spermatozoa from men and cynomolgus monkeys. Mol Reprod Dev. 1997; 48:267-275.(J. Michael Bedford, Vet M)
Hermo L, Adamali HI, Trasler JM. Postnatal development and regulation of ?-hexosaminidase in epithelial cells of the rat epididymis. J Androl. 2004 ;25:69-81.
In the present issue, Hermo et al illustrate in an elegant way for the rat epididymis the postnatal development of ?-hexosaminidase activity localized to epithelial lysosomes and the effects of orchiectomy and efferent duct ligation on its expression in different regions and in different cell types. This most recent study of epididymal ?-hexosaminidase is one of a series in which classic techniques of cell biology are used in attempts to better define the character of the epididymal epithelium. However, an earlier paper from these authors (Trasler et al, 1998) showed that some young male mice lacking the ?-hexosaminidase gene develop some epididymal abnormalities but do remain fertile. This should give us pause, perhaps, to reflect briefly on current epididymal research—how can this best be approached, and what should be its priorities? Can random studies, whether involving gene expression or histochemistry, lead us in the foreseeable future to an understanding of the key molecular events of sperm maturation or the maintenance of sperm viability (storage) in the epididymis and, perhaps, to an ability to manipulate these functions—the main issues that would seem to justify its pursuit?
In addition to studies of the epithelium of the epididymis, microsampling of different regions has shown much about its changing ionic profile and about a variety of components that include many proteins, in particular, as well as glycoprotein modifying enzymes, glycerol-phosphocholine, inositol, carnitine, and others (Brooks, 1990). At the same time, investigation during the past 4 decades has provided a fertility profile for the epididymis in a few mammalian species and has detected several changes in the sperm cell that seem linked to its fertilizing ability: the cross-linking of protein-bound thiols, the change in the form of the acrosome and/or the character of its content, and, observed 90 years ago, the onset of the capacity for progressive motility that is related in part to certain metabolic enzymes of the sperm tail but probably also to change(s) in its plasmalemma. Some facets of the maturation process can occur independently of others. For example, rabbit spermatozoa withheld in the upper epididymis can for a limited period express the potential for prolonged optimal motility yet lack the ability to bind to the zona in the fallopian tube. Similarly, structural cross-linking of sperm thiols occurs readily in nonspecific conditions in vitro.
Despite this background information, it remains difficult to assign a specific function to most molecules in epididymal secretions. With the possible exception of the physical constraints brought by "immobilin" in some murid rodents at least, it has proven difficult to connect any single luminal factor to the cauda's ability to prolong the viability of mature spermatozoa. The evidence with regard to fertilizing ability does give a sense that the final key to this lies in certain changes that occur in the sperm plasmalemma. Nonetheless, the multifaceted nature of maturation brings into question whether a single component of the environment could be responsible, as a final "switch on," so to speak. Among the few examples of particular molecules that do seem to relate to the events of fertilization, a cysteine-rich secretory protein (CRISP) elaborated by and acquired in the caput appears to participate in gamete fusion (Ellerman et al, 2002), though it remains to be seen whether this is an essential factor—whether spermatozoa from males lacking its gene are unable to fertilize. In the hamster (and human?), a secretory caput glycoprotein (P26h) that associates with the periacrosomal surface appears to be a key ligand for the zona pellucida (Sullivan, 1999); in the mouse also, a protein (SED1) secreted by caput principle (sic) cells is reported to mediate initial binding to the zona (Ensslin and Shur, 2003). However, spermatozoa from some mice lacking the gene for SED1 can fertilize, in contrast to the complete inability of immature caput or noncapacitated populations, for example. This again raises the possibility discussed by Castle (2002) of some redundancy with regard to zona-binding elements on the sperm surface.
Among the difficulties involved in identifying the key features of sperm maturation and storage at a molecular level is the subtle but real problem of the present need to frame questions about many aspects of mammalian gamete function within something of a conceptual vacuum. On the basis of the little that is known about the Wolffian duct in other vertebrates, the evidence points to a leap in the complexity of its role(s) during the evolution of therian mammals. However, it is still far from clear why the final maturation of mammalian spermatozoa should involve a greater variety of posttesticular cellular changes and why at least some of these depend acutely on the environment created in the epididymis. It is equally difficult to understand what has driven the evolution of a specialized system of sperm storage in the cauda that is closely regulated by testicular androgen and usually by a lower-than-body temperature—but only in the mammalian line—with possible implications, in turn, for sperm capacitation and for evolution of the scrotum (Bedford, in press).
Such a lack of basic understanding about the state of this duct system makes it more difficult to ask the right questions and interpret results. Indeed, much epididymal research seems to exemplify the dictum of the molecular biologist Sydney Brenner, who argues that the great challenge in biology today is the turning of data into understanding as to function. While emphasis should perhaps be given as far as possible to the linking of research on the epididymis more directly to its functions, other difficulties present themselves in trying to understand the role of particular components in its fluids. Not only does sampling and analysis of the upper levels of the epididymis require special expertise, but the precise nature of the changes that spermatozoa undergo there can vary from species to species. For example, the cholesterol-phospholipid ratio in the sperm plasmalemma appears to increase during epididymal transit in the ram and goat, remains constant in the boar, and decreases in the rat and stallion (Cross, 1998). This suggests that a functional end point can be arrived at through different molecular means. At the same time, it can be a problem to interpret function even in a general way. For instance, it has been unclear in many cases whether a particular change in the sperm plasmalemma or a particular component of the environment might relate to the maturation of spermatozoa or, alternatively, to the maintenance of their viability. A focus on the developing ability to fertilize has created a tendency to think of the epididymis and its milieu primarily in terms of sperm maturation. However, it is very probable that major elements of the change(s) that the plasmalemma of the spermatozoon undergoes in the epididymis relate to its viability in the cauda and that much of the length of the duct could be devoted to preparation for maintaining that, rather than its maturation. For instance, some sperm membrane components first expressed in the mid-region of the epididymis constitute receptors for surface proteins acquired later as spermatozoa reach the cauda (HIS protein, Rifkin and Olson, 1985; CD52, Yeung et al, 1997). Furthermore, although the latter proteins were first thought to relate to sperm maturation, in the rat, rabbit, dog, and sheep at least, their expression and binding to a generally mature population first in the upper cauda suggest a tie to the events of storage.
Finally, among the models that might help us probe some of these questions, one that may be worth exploring further is the cryptepididymal male. In murid rodents and the rabbit, at least, the epididymis can be reflected to the abdomen, leaving a normal testis in the scrotum. This reconfiguration of the epididymis provides an experimental situation in which sperm maturation continues normally but in which the storage function is immediately suppressed. Deep body temperature does not seem to significantly affect the ultrastructure of the cauda epithelium, but it has easily discernible effects on fluid and ion transport across it, on the ionic and macromolecular composition of its luminal secretion, and even on gene expression in a limited way. It is possible that, perhaps together with some modulation of androgen levels, this model may provide a situation in which to probe the elements that are critical for the viability/storage of epididymal spermatozoa as distinct from those involved in their maturation.
References
Bedford JM. Enigmas of mammalian gamete form and function. Biol Rev. In press.
Brooks DE. Biochemistry of the male accessory glands. In: Lamming GE, ed. Marshall's Physiology of Reproduction. Vol 2 . London: Churchill Livingstone; 1990:569-690.
Castle PE. Could multiple low-affinity bonds mediate primary sperm-zona pellucida binding? Reproduction. 2002; 124:29-32.
Cross N. Role of cholesterol in sperm capacitation. Biol Reprod. 1998;59:7-11.
Ellerman DA, Da Ros VG, Cohen DJ, Busso D, Morgenfeld MM, Cuasnicu PS. Expression and structure function analysis of de, a sperm cysteine-rich protein that mediates gamete fusion. Biol Reprod. 2002; 67:1225-1231.
Ensslin MA, Shur BD. Identification of mouse sperm SED 1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell. 2003;114:405-417.
Rifkin JM, Olson GE. Characterization of maturation-dependent extrinsic proteins of the rat sperm surface. J Cell Biol. 1985;100:1582-1591.
Sullivan R. Interaction between sperm and epididymal secretory protein. In: Gagnon C, ed. The Male Gamete—From Basic Science to Clinical Applications. Vienna, Ill: Cache River Press; 1999 : 93-104.
Trasler JM, Saberi F, Somani IH, et al. Characterization of the testis and epididymis in mouse models of human Tay Sachs and Sandhoff diseases and partial determination of accumulated gangliosides. Endocrinology. 1998; 139:3280-3288.
Yeung CH, Schroter S, Wagenfeld A, et al. Interaction of human epididymal protein CD52 (HE5) with epididymal spermatozoa from men and cynomolgus monkeys. Mol Reprod Dev. 1997; 48:267-275.(J. Michael Bedford, Vet M)