Keith A. Sutton

Regulating the acrosome reaction

The acrosome reaction is a secretory event that must be completed by the sperm of many animal species prior to fusion with eggs. In mammals, exocytosis in triggered by ZP3, a glycoprotein component of the egg pellucida, following gamete contact. ZP3 promotes a sustained influx of Ca2+ into sperm that is necessary for the acrosome reaction. Here, we discuss the mechanism by which ZP3 generates Ca2+ entry, as well as the upstream events leading to this influx and downstream processes that couple it with exocytosis.

A polycystin-1 controls postcopulatory reproductive selection in mice

Pkdrej, a member of the polycystin-1 gene family, is expressed only in the male germ line. Male mice that are homozygous for a targeted mutation in the Pkdrej allele (Pkdrejtm/tm) are fertile in unrestricted mating trials, but exhibit lower reproductive success when competing with wild-type males in sequential mating trials and in artificial insemination of mixed-sperm populations. Following mating, sperm from Pkdrejtm/tm mice require >2 h longer than those of wild-type males to be detected within the egg/cumulus complex in the oviduct. Sperm from mice of both genotypes are able to capacitate in vitro. However, one of the component processes of capacitation, the ability to undergo a zona pellucida–evoked acrosome reaction, develops more slowly in sperm from Pkdrejtm/tm animals than in sperm from wild-type males. In contrast, a second component process of capacitation, the transition to hyperactivated flagellar motility, develops with a similar time course in both genotypes. These two behavioral consequences of capacitation, exocytotic competence and altered motility, are therefore differentially regulated. These data suggest that Pkdrej controls the timing of fertilization in vivo through effects on sperm transport and exocytotic competence and is a factor in postcopulatory sexual selection.

Functional characterization of PKDREJ, a male germ cell-restricted polycystin.

Polycystin‐1 regulates a number of cellular processes through the formation of complexes with the polycystin‐2 ion channel or with other signal transduction proteins. Polycystin‐1 is expressed in many tissues but other members of this gene family are distributed in a more restricted fashion. PKDREJ expression has been detected only in the mammalian testis, where it is restricted to the spermatogenic lineage and retained in mature sperm. However, the functional characteristics of this protein and its role in sperm biology are not well understood. In this study it is shown that PKDREJ can modulate G protein signaling and associates with several members of the polycystin‐2 family. These interactions, as well as polycystin‐2 association with TRPC channels, are consistent with a role of this protein in the regulation of the acrosome reaction and in other aspects of sperm physiology. J. Cell. Physiol. 209: 493–500, 2006.

In the Beginning: Lessons from Fertilization in Mice and Worms

Sexual reproduction proceeds by fertilization; formation of new individuals by the union of haploid gametes. Recent reports in Cell and in Developmental Cell may provide new insights as to how this process begins and is regulated.

Metabolic Substrates Exhibit Differential Effects on Functional Parameters of Mouse Sperm Capacitation

ABSTRACT Although substantial evidence exists that sperm ATP production via glycolysis is required for mammalian sperm function and male fertility, conflicting reports involving multiple species have appeared regarding the ability of individual glycolytic or mitochondrial substrates to support the physiological changes that occur during capacitation. Several mouse models with defects in the signaling pathways required for capacitation exhibit reductions in sperm ATP levels, suggesting regulatory interactions between sperm metabolism and signal transduction cascades. To better understand these interactions, we conducted quantitative studies of mouse sperm throughout a 2-h in vitro capacitation period and compared the effects of single substrates assayed under identical conditions. Multiple glycolytic and nonglycolytic substrates maintained sperm ATP levels and comparable percentages of motility, but only glucose and mannose supported hyperactivation. These monosaccharides and fructose supported the full pattern of tyrosine phosphorylation, whereas nonglycolytic substrates supported at least partial tyrosine phosphorylation. Inhibition of glycolysis impaired motility in the presence of glucose, fructose, or pyruvate but not in the presence of hydroxybutyrate. Addition of an uncoupler of oxidative phosphorylation reduced motility with pyruvate or hydroxybutyrate as substrates but unexpectedly stimulated hyperactivation with fructose. Investigating differences between glucose and fructose in more detail, we demonstrated that hyperactivation results from the active metabolism of glucose. Differences between glucose and fructose appeared to be downstream of changes in intracellular pH, which rose to comparable levels during incubation with either substrate. Sperm redox pathways were differentially affected, with higher levels of associated metabolites and reactive oxygen species generated during incubations with fructose than during incubations with glucose.

Shedding light on sperm pHertility

The acquisition of fertilization capacity by sperm is regulated by intracellular pH (pH(i)), but the transport pathways that regulate pH(i) are not well understood. Lishko et al. (2010) now report that Hv1, the voltage-sensitive proton channel, is present in human sperm and is an important regulator of the functional maturation of sperm.

How to attract a sperm

One of the most fundamental questions of fertilization is how do sperm locate eggs? In many animals and lower plant groups, sperm are guided by chemo-attractants released from eggs. In this issue of Nature Cell Biology, Kaupp and colleagues now examine the very early events of this process in the sea urchin Arbacia punctulata.

Evolution of the voltage sensor domain of the voltage-sensitive phosphoinositide phosphatase, VSP/TPTE, suggests a role as a proton channel in eutherian mammals

The voltage-sensitive phosphoinositide phosphatases provide a mechanism to couple changes in the transmembrane electrical potential to intracellular signal transduction pathways. These proteins share a domain architecture that is conserved in deuterostomes. However, gene duplication events in primates, including humans, give rise to the paralogs TPTE and TPTE2 that retain protein domain organization but, in the case of TPTE, have lost catalytic activity. Here, we present evidence that these human proteins contain a functional voltage sensor, similar to that in nonmammalian orthologs. However, domains of these human proteins can also generate a noninactivating outward current that is not observed in zebra fish or tunicate orthologs. This outward current has the anticipated characteristics of a voltage-sensitive proton current and is due to the appearance of a single histidine residue in the S4 transmembrane segment of the voltage sensor. Histidine is observed at this position only during the eutherian radiation. Domains from both human paralogs generate proton currents. This apparent gain of proton channel function during the evolution of the TPTE protein family may account for the conservation of voltage sensor domains despite the loss of phosphatase activity in some human paralogs.

If music be the food of love...

The link between hearing and reproduction has been made before, as in William Shakespeares Twelfth Night. Now, a paper in the current issue of Nature Cell Biology demonstrates that these two processes have an unforeseen degree of structural similarities.

What can we learn about fertilization from cystic fibrosis

It is a curious and intriguing situation that mammalian sperm are introduced into the female reproductive tract in an infertile state and must be educated there before they are able to fertilize oocytes. The recognition that mammalian sperm must first be switched into a competent state, or capacitated, was exploited in the development of in vitro fertilization methods and has proved essential for the dependent technologies of clinical assisted reproduction and infertility treatments. Yet many aspects of the mechanisms of capacitation remain unclear (for recent reviews, see refs. 1 and 2). In a recent issue of PNAS, Xu et al. (3) advanced our understanding of capacitation by showing that CFTR, the cystic fibrosis transmembrane regulator, plays an essential role in some aspects of this process.