SPERM FACTORS AND EGG ACTIVATION: Divergent sperm factors for egg activation in amphibian fertilization

in Reproduction
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  • 1 Laboratory of Reproductive Developmental Biology and Developmental Cell Biology, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yamaguchi, Japan

Correspondence should be addressed to Y Iwao; Email: iwao@yamaguchi-u.ac.jp

This paper forms part of an anniversary issue on the 20th Anniversary of PLCZ1. The Guest Editor for this section was Professor Karl Swann, Cardiff University, UK

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Mature amphibian eggs arrested at meiotic metaphase II must undergo activation to initiate embryonic development soon after fertilization. Fertilizing sperm provide eggs with a signal that induces egg activation, and an increase in intracellular Ca2+ concentration in the egg cytoplasm (a Ca2+ rise) is the most important signal for this initiation. The sperm transmits the signal for the Ca2+ rise, known as the sperm factor, which is divergent between anurans and urodeles. In monospermic anurans, the sperm transmits the signal through a receptor on the egg membrane, causing a single rapid Ca2+ rise. Sperm matrix metalloproteinase-2 is a potential candidate for the receptor-mediated sperm factor in anurans. In physiologically polyspermic urodeles, multiple slower Ca2+ rises are caused by a soluble sperm factor (sperm-specific citrate synthase) which is transferred to the egg cytoplasm after sperm–egg fusion. We discuss the molecular mechanisms of egg activation in amphibian fertilization, focusing on recent progress in characterizing these sperm factors and their divergence during the evolution of tetrapod vertebrates.

Abstract

Mature amphibian eggs arrested at meiotic metaphase II must undergo activation to initiate embryonic development soon after fertilization. Fertilizing sperm provide eggs with a signal that induces egg activation, and an increase in intracellular Ca2+ concentration in the egg cytoplasm (a Ca2+ rise) is the most important signal for this initiation. The sperm transmits the signal for the Ca2+ rise, known as the sperm factor, which is divergent between anurans and urodeles. In monospermic anurans, the sperm transmits the signal through a receptor on the egg membrane, causing a single rapid Ca2+ rise. Sperm matrix metalloproteinase-2 is a potential candidate for the receptor-mediated sperm factor in anurans. In physiologically polyspermic urodeles, multiple slower Ca2+ rises are caused by a soluble sperm factor (sperm-specific citrate synthase) which is transferred to the egg cytoplasm after sperm–egg fusion. We discuss the molecular mechanisms of egg activation in amphibian fertilization, focusing on recent progress in characterizing these sperm factors and their divergence during the evolution of tetrapod vertebrates.

Introduction

During amphibian fertilization, a fertilized egg must undergo activation in an appropriate period for the initiation of embryonic development with a diploid configuration. Precocious activation before sperm entry causes parthenogenetic development, while a delay in egg activation results in polyspermy due to the failure to prevent additional sperm entry, termed polyspermy block (Iwao 2000, Iwao & Izaki 2018, Iwao & Watabe 2020, Wozniak & Carlson 2020). The cell cycle of unfertilized amphibian eggs is arrested at meiotic metaphase II. After egg activation induced by the fertilizing sperm, the eggs resume and complete meiosis to undergo cleavage (mitotic cell division). Polyspermy blocks induced by egg activation are indispensable for ensuring normal development of a diploid genome, and several of these are initiated by egg activation after the entry of the primary sperm (Iwao & Izaki 2018, Iwao & Watabe 2020, Wozniak & Carlson 2020). An increase in intracellular Ca2+ concentration ([Ca2+]i) in the egg cytoplasm is the most important signal for egg activation initiation (Iwao 2012, Iwao & Izaki 2018). An artificial increase in [Ca2+]i by pricking with a fine needle or by treatment with a Ca-ionophore can induce egg activation, resulting in parthenogenesis in some species.

The mode of fertilization varies among amphibian species. Most anurans (frogs and toads) exhibit monospermy in which only one sperm is allowed to enter an egg, whereas most urodeles (newts and salamanders) exhibit physiological polyspermy, whereby only one sperm nucleus is selected to form a zygote nucleus in the egg cytoplasm after the incorporation of several sperm (Iwao 2012, Iwao & Izaki 2018, Iwao et al. 2020). The different mechanisms of egg activation appear to be acquired with the evolution of the fertilization mode. In monospermic species, prompt initiation of egg activation is necessary to prevent extra sperm from entering the egg. In contrast, physiologically polyspermic species have slower action to allow several sperm to enter the egg. In this respect, egg activation in monospermic species is mediated by a ligand on the sperm membrane that interacts with its receptor on the egg plasma membrane, known as the receptor-mediated sperm factor. In contrast, egg activation caused by a sperm factor transferred from the sperm after sperm–egg fusion, called a soluble sperm factor is suited to physiologically polyspermic urodeles. We discuss the molecular mechanisms underlying the increase in [Ca2+]i (the Ca2+ rise), focusing on recent progress in characterizing these sperm factors during divergent fertilization in amphibians.

A receptor-mediated sperm factor for egg activation in monospermic anurans

The Ca2+ rise in the egg cytoplasm is a main signal both necessary and sufficient for egg activation in monospermic anurans. The suppression of the increase in [Ca2+]i during fertilization inhibits egg activation (Kline 1988), and an artificial increase in [Ca2+]i causes egg activation without stimulation by sperm (Iwao & Masui 1995, Watabe et al. 2019). The Ca2+ rise during fertilization consists of two phases in the African clawed frog, Xenopus laevis and the western clawed frog, X. tropicalis. The first is an initial small Ca2+ rise (IS Ca2+-rise), detected as a hot spot around the sperm entry site (Fig. 1A, Fontanilla & Nuccitelli 1998, Runft et al. 1999, Fees & Stith 2019). The second is a wave-like Ca2+ rise (Ca2+ wave) amounting to 1.1–2.2 μM and propagating with a velocity of 2.1–8.9 μm/s over the entire egg cytoplasm after the IS Ca2+ rise (Fig. 1; Busa & Nuccitelli 1985, Grandin & Charbonneau 1991, Nuccitelli et al. 1993, Fontanilla & Nuccitelli 1998, Iwao et al. 2014, Fees & Stith 2019, Watabe et al. 2019). In X. laevis, the IS Ca2+ rise occurs in a small area of approximately 25 μm in diameter in the egg cortex, and the propagation of a Ca2+ wave is observed within ~30 s after hot spot appearance (Fees & Stith 2019). A similar IS Ca2+ rise was detected in voltage clamping of both X. laevis and X. tropicalis eggs as a small initial step-like current (IS current), which is due to the opening of Ca2+-activated Cl-channels (Glahn & Nuccitelli 2003, Watabe et al. 2019). The IS current continues 2.5–8.8 s before the start of a progressive increase in inward current due to the propagative Ca2+ wave (Watabe et al. 2019). A Ca2+ store, the endoplasmic reticulum (ER) is abundantly distributed in the cortex of Xenopus eggs (Campanella & Andreuccetti 1977, Terasaki et al. 2001, El-Jouni et al. 2005). Cortical ER consists of patches approximately 20 μm in diameter with clustered inositol 1,4,5-trisphosphate receptors (IP3-R) to release Ca2+ from the ER (Fig. 2; Machaca 2004). The area of a hot spot in the IS Ca2+ rise corresponds to that of a cortical ER patch (Fees & Stith 2019), indicating the release of Ca2+ ions from that patch.

Figure 1
Figure 1

Ca2+ rises during egg activation in amphibians. (A) A Ca2+ wave in an egg of the monospermic anuran, Xenopus, showing the IS Ca2+ rise at the entry site of a single sperm followed by a Ca2+ wave spreading throughout the egg cytoplasm for 10–20 min after fertilization. (B) Multiple Ca2+ waves in an egg of the physiologically polyspermic urodele, Cynops, showing propagation of each Ca2+ wave preceded by a spike-like Ca2+ rise (Ca2+ spike) in approximately 25% of the egg cytoplasm for 30–40 min after fertilization.

Citation: Reproduction 164, 1; 10.1530/REP-21-0480

Figure 2
Figure 2

A schematic model of a signaling cascade by the receptor-mediated sperm factor in egg activation of the monospermic anuran, Xenopus. Positively charged hemopexin domain of MMP-2 (MMP-2 HPX) on the sperm head binds to negatively charged ganglioside GM1 (GM1) on the microdomain (MD) in egg plasma membrane (PM), resulting in the activation of Src kinase (Src) to stimulate phospholipase C gamma (PLCG). Inositol 1, 4, 5-trisphosphate (IP3) produced by PLCG induces the IS Ca2+ rise through a cluster of IP3-receptors (IP3-R) in a patch of cortical ER (cER). MMP-2 HPX could bind integrins to transmit a signal for Ca2+ influx. IS Ca2+ rise induces Ca2+ release through cER to propagate a Ca2+ wave. In another case, a tryptic protease on the sperm colocalized with sperm-surface glycoprotein (SGP) and MMP-2 cleaves an egg receptor, Uroplakin III (UPIII) associated with UPIb, resulting in the activation of Src kinase. Phosphatidic acid (PA) produced by the activation of phospholipase D1b (PLD1b) may be involved in the activation of Src kinase.

Citation: Reproduction 164, 1; 10.1530/REP-21-0480

In Xenopus fertilization, the activation of phospho­lipase C gamma (PLCG) stimulates the production of IP3, which binds IP3-R onto the ER to release Ca2+ (Fig. 2; Busa et al. 1985, Stith et al. 1993, 1994, Snow et al. 1996). IP3 produced by PLCG around the sperm entry site likely induces the IS Ca2+ rise (Nuccitelli et al. 1993, Sato et al. 2003, Wozniak et al. 2018), and Ca2+ waves propagate through the sensitization of clustered IP3 receptors in each patch by a local increase in [Ca2+]i and/or by the activation of adjacent PLCG to produce IP3 (Fig. 2). During fertilization, PLCG is activated by a protein tyrosine kinase, Src homology 2-containing adaptor protein Src (Src) kinase (Fig. 2; Sato et al. 1999, 2002, Mahbub Hasan et al. 2005, Sakakibara et al. 2005). Src kinase localizes in membrane microdomains, that is, low-density, detergent-insoluble membrane fractions, and is activated by phosphorylation within 1 min of fertilization (Sato et al. 1996). PLCG is tyrosine phosphorylated by Src kinase and translocated from the cytoplasm to the membrane to produce IP3 (Sato et al. 2000, Tokmakov et al. 2002, 2014, Sato et al. 2003). Thus, activation of Src kinase by the fertilizing sperm is the most important step in the Ca2+ rise necessary for egg activation (Sato 2018).

What is the sperm factor for the activation of Src kinase during anuran fertilization? The sperm factor is probably a ligand molecule on the sperm membrane that interacts with an egg receptor around sperm-egg binding and/or fusion because the IS Ca2+-rise (IS current) can occur less than one second after the release of fertilization blocks by the positive membrane potential (Watabe et al. 2019). It is much faster than that induced by a soluble sperm factor in mouse eggs, in which initial Ca2+ rise is initiated 1–3 min after sperm–egg fusion (Lawrence et al. 1997). There are several candidates for the receptor-mediated sperm factor for the initiation of IS Ca2+-rise. First, matrix metalloproteinase-2 (MMP-2) on the sperm membrane is closely involved in the IS Ca2+ rise. MMP-2 is localized in the anterior tip of the sperm head (Watabe et al. 2021) where the sperm binds and fuses with the egg plasma membrane (Boyle et al. 2001). Sperm MMP-2 is indispensable for voltage-dependent egg activation and sperm entry with a fast, electrical block to polyspermy during Xenopus fertilization (Iwao et al. 2014, Watabe et al. 2021). In mutant X. tropicalis frogs deficient in the mmp2 gene, the deletion of MMP-2 protein on the sperm decreases voltage sensitivity in both voltage-dependent egg activation and sperm entry (Watabe et al. 2021). Sperm MMP-2 regulates the IS Ca2+ rise during egg activation, as well as sperm–egg membrane fusion. MMP-2-deficient sperm can activate the egg, possibly because of the redundancy of MMPs. In X. laevis, a partial amino acid sequence of the hemopexin domain (HPX) in MMP-2 (HPX-A peptide, GMSQIRGETFFFK) is positively charged and its application on the egg surface causes egg activation accompanied by a Ca2+ rise in a voltage-dependent manner similar to that by fertilizing sperm (Iwao et al. 2014). A positively charged HPX-A peptide can bind a negatively charged ganglioside GM1 enriched in the microdomain of the egg plasma membrane (Fig. 2;Iwao et al. 2014). Extracellular application of ganglioside GM1 inhibits Xenopus fertilization and egg activation (Mahbub Hasan et al. 2014). The binding of MMP-2 HPX to ganglioside GM1 might induce the activation of Src kinase colocalized in membrane microdomains, resulting in a Ca2+ rise. In another signal cascade, MMP-2 HPX containing an RGE sequence similar to an integrin-binding motif (RGD) might interact with integrins on the egg plasma membrane to transmit a signal for the Ca2+ rise. MMP-2 binds to integrin on the cell membrane (Brooks et al. 1996) and facilitates the cleavage of the extracellular domain of protease-activated receptor 1 to activate the G protein cascade involving Ca2+ influx (Sebastiano et al. 2017). Xenopus eggs are activated by an RGDS peptide (Iwao & Fujimura 1996, Sato et al. 1999) or by a partial peptide (CMRPKTEC) of the Xenopus metalloprotease/disintegrin/cysteine-rich domain 16 (xMDC16; Shilling et al. 1997, 1998). The RGDS peptide also induces protein tyrosine phosphorylation in the egg but does not induce egg activation in the South American toad, Rhinella (Bufo) arenarum (Mouguelar et al. 2011). However, the activation by the RGDS peptide is independent of voltage (Iwao & Fujimura 1996). xMDC16 protein is localized on the posterior region of the sperm head and the voltage-dependency activated by the xMDC16 peptide differs from that by the sperm. Therefore, one of these is unlikely to be the sperm factor for egg activation, and sperm MMP-2 is the most potential candidate for Xenopus fertilization. MMPs are involved in sperm–egg fusion during fertilization of sea urchins (Roe et al. 1988, Kato et al. 1998), ascidians (De Santis et al. 1992), and mice (Correa et al. 2000). In addition, a local Ca2+ rise regulates successful membrane fusion with sperm in sea urchin eggs (McCulloh et al. 2000, Ivonnet et al. 2017). Thus, sperm MMP-2 could provide a universal function in egg activation and membrane fusion during animal fertilization.

The second candidate is the single-transmembrane protein, uroplakin III (UPIII), which is localized in membrane microdomains in association with uroplakin Ib (UPIb) (Fig. 2; Sakakibara et al. 2005, Mahbub Hasan et al. 2007, 2011). UPIII is tyrosine-phosphorylated during fertilization through partial proteolysis of GRR sequence. Phosphorylated UPIII appears to induce egg activation (Ca2+ rise) by activation of Src kinase/PLCγ kinase (Mahbub Hasan et al. 2005, 2014). Xenopus eggs are artificially activated by treatment with sperm tryptic protease or cathepsin B with proteolytic activity against the GRR sequence (Mizote et al. 1999). Since the sperm tryptic protease appears to be colocalized with sperm-surface glycoprotein and MMP-2 (Nagai et al. 2009, Iwao et al. 2014), it is of interest to investigate its role in Ca2+ rise in cooperation with MMP-2.

In other cascades, phospholipase D1b in the egg cytoplasm is activated to produce phosphatidic acid (PA) from phosphatidylcholine during Xenopus fertilization (Bates et al. 2014, Stith 2015). Treatment with PA activates Src kinase and slowly induces a hot spot-like Ca2+ rise followed by a propagative Ca2+ wave (Fees & Stith 2019). In R. arenarum, the phospholipase A2 pathway could be involved in egg activation through the release of arachidonic acid from phospholipids in the ER to induce Ca2+ release (Ajmat et al. 2013). However, it remains unknown whether fertilizing sperm stimulate these phospholipases. In addition, there are several reports on soluble sperm factors for egg activation in anurans. Although injection of Xenopus sperm extracts can induce Ca2+ rise (oscillations) in mouse eggs (Dong et al. 2000), its injection into homologous eggs does not cause egg activation (Harada et al. 2011). In R. arenarum, egg activation is induced by injection of a 24 kDa fraction of sperm extract into the egg or by the application of a 36 kDa fraction on the egg surface (Bonilla et al. 2008). The 24 kDa fraction contains PLC activity, but the amount of PLC is insufficient for a single sperm to induce egg activation (Bonilla et al. 2014). Taken together, egg activation in anurans is unlikely to be caused by soluble sperm factors.

A soluble sperm factor for egg activation in physiologically polyspermic urodeles

In urodele amphibians exhibiting physiologically polyspermy, such as the newts, Cynops pyrrhogaster (Yamamoto et al. 1999, 2001, Harada et al. 2011) and Pleurodeles waltl (Grandin & Charbonneau 1992), [Ca2+]i in egg cytoplasm increases up to 0.15 μM during fertilization, which is both necessary and sufficient for egg activation. Prevention of the Ca2+ rise inhibits all activation events, while an artificial Ca2+ increase by Ca-ionophore causes egg activation (Charbonneau et al. 1983, Iwao & Masui 1995, Yamamoto et al. 1999). A spike-like rise in [Ca2+]i (Ca2+ spike) occurs around the sperm entry site, followed by a longer duration Ca2+ wave during fertilization (Fig. 1B; Harada et al. 2011). The Ca2+ wave propagates in approximately 25% of the hemisphere with a velocity of 5.1 μm/s for 30–40 min. Although each fertilizing sperm causes relatively small Ca2+ waves, each wave propagates over the entire egg cortex by the entry of several sperm into the egg (Fig. 1B).

The spike-like Ca2+ rise was probably induced by a sperm protease on the egg surface. A similar increase is elicited by the application of a sperm extract containing an acrosomal tryptic protease on the egg surface (Mizote et al. 1999, Harada et al. 2011). The Ca2+ spike is due to the release of Ca2+ ions from intracellular Ca2+ stores around the sperm-binding site, as via the PAR-like receptor, but is insufficient for producing the Ca2+ wave to cause egg activation (Harada et al. 2011). ER is sparse in the cortex of C. pyrrhogaster eggs and a major Ca2+ rise during fertilization is due to the release of Ca2+ ions from the ER located in the internal egg cytoplasm. In contrast to anuran eggs, a local increase in [Ca2+]i induced by pricking does not cause egg activation in most urodele species.

The long-duration Ca2+ wave is caused by a different mechanism from that of the Ca2+ spike. The Ca2+ wave is induced by a soluble sperm factor transferred from the sperm to the egg after sperm–egg fusion. Injection of the sperm extract into the egg causes the propagation of a Ca2+ wave with a velocity of approximately 6.2 μm/s in the absence of an initial Ca2+ spike (Yamamoto et al. 2001, Harada et al. 2007, 2011, Ueno et al. 2014). The velocity of Ca2+ waves induced by the sperm extract was similar to that by fertilizing sperm. The injection of sperm extract equivalent to one sperm can activate 24% of the eggs (Harada et al. 2011), indicating that a sufficient amount of sperm factor is incorporated into the egg by penetration of several sperm during polyspermic fertilization. Sperm-specific citrate synthase (sCS) is a main component of the soluble sperm factor in C. pyrrhogaster. sCS exhibits a lower mobility (45 kDa) than ordinary CS (43 kDa) expressed in somatic cells following SDS-PAGE, which is due to the phosphorylation of sCS (Ueno et al. 2014). Injection of not only protein but also mRNA of CS induces a Ca2+ increase that causes egg activation (Harada et al. 2007). A large amount of extra-mitochondrial sCS is localized in the midpiece of the sperm and is dispersed in the egg cytoplasm after the incorporation of the entire sperm (Fig. 3; Ueno et al. 2014). Thus, sCS is a major component of the soluble sperm factor for egg activation during urodele fertilization.

Figure 3
Figure 3

A schematic model of a signaling cascade by the soluble sperm factor in egg activation of physiologically polyspermic urodele, Cynops. A sperm tryptic protease induces a spike-like Ca2+ rise (Ca2+ spike) via a putative PAR-like receptor on egg plasma membrane (PM). In addition, sperm-specific citrate synthase (sCS) is transferred from each sperm into the egg cytoplasm. (1) sCS may causes the Ca2+ release from the inner ER or from mitochondria by acetyl-CoA (aCoA) or oxaloacetate (OA). (2) sCS may stimulate ATP production to induce Ca2+ release through IP3-R. ER with IP3-R and PLCγ are concentrated along the astral microtubules in sperm asters to form a signal center of Ca2+ wave.

Citation: Reproduction 164, 1; 10.1530/REP-21-0480

How does sCS trigger Ca2+ increase in urodele eggs? First, the enzymatic activity of sCS is probably necessary for the propagation of Ca2+ waves by the sperm extract (Harada et al. 2011). Activation by the sperm factor is prevented by a CS inhibitor, palmitoyl CoA, whereas the injection of acetyl-CoA or oxaloacetate causes egg activation. CS produces citrate from acetyl-CoA and oxaloacetate in the mitochondrial citric acid (TCA) cycle, but acetyl-CoA and oxaloacetate might be inversely produced by sCS from citrate that is abundant in the egg cytoplasm (Fig. 3). The Ca2+ rise by the sperm factor is mediated by Ca2+ release from the ER through IP3-receptors (Yamamoto et al. 2001). It is known that IP3-receptors on the ER are sensitized by acetyl CoA (Missiaen et al. 1997). Although injection of citrate lyase which catalyzes the cleavage of citrate to oxaloacetate and acetate causes egg activation in C. pyrrhogaster, it remains to be determined whether these molecules are produced in the egg cytoplasm during fertilization.

Secondly, we have recently demonstrated that extra-mitochondrial CS (eCS) transferred from fertilizing sperm induces repetitive Ca2+ rises (oscillations) in mouse eggs (Kang et al. 2020). The eCS might function as a sole CS related to the TCA cycle in the extra-mitochondrial space (Fig. 3). ATP production driven by eCS could trigger the Ca2+ rise from intracellular storage in the egg cytoplasm because Ca2+ release from the IP3-receptor is enhanced by ATP (Missiaen et al. 1997). The role of sCS in ATP production is of interest in clarifying the mechanism of Ca2+ rise during egg activation in urodele fertilization.

Thirdly, sCS in the midpiece region of sperm is dispersed in the egg cytoplasm around the sperm entry site in association with microtubules (Fig. 3; Ueno et al. 2014). Microtubules in the egg cytoplasm, such as sperm asters, are necessary for the propagation of Ca2+ waves since this propagation is inhibited by the depolymerization of microtubules (Ueno et al. 2014). Interestingly, sCS, but not CS accumulation in eggs during oogenesis, is associated with microtubules in the egg cytoplasm. Phosphorylated sCS appears to be closely associated with sperm asters during the propagation of Ca2+ waves (Fig. 3; Ueno et al. 2014). sCS also colocalizes with PLCG and IP3 receptors around sperm nuclei (Ueno et al. 2014). Since β-tubulin can bind to Src homology 2 domains (Itoh et al. 1996) and pleckstrin homology (PH) domains of PLCγ (Chang et al. 2005) to promote its activity, we proposed a model in which Ca2+ waves are propagated by the accumulation of PLCG and ER with IP3 receptors along astral microtubules by sCS (Ueno et al. 2014). We proposed three models for the Ca2+ rise by sCS, but further investigation is necessary to determine their relationship between the initial Ca2+ rise and the propagative Ca2+ wave. Thus, sCS plays an important role in the signal center of Ca2+ waves during egg activation in urodele amphibians.

Conclusions and perspectives

We have described the mechanisms of the sperm factors required for egg activation among amphibians, suggesting a change in sperm factors concomitant with the transition in the mode of fertilization during the evolutionary process. Anuran amphibians have improved the receptor-mediated sperm factor to ensure monospermy by a fast, electrical block to polyspermy. The initiation of Ca2+ rise and membrane fusion between a sperm and an egg are closely connected in anurans, indicating the lack of a soluble sperm factor. In the primitive urodele, Hynobius. nebulosus exhibiting monospermy (Iwao 1989), the egg undergoes activation not only in response to a local Ca2+ rise by pricking or by the receptor-mediated signal by RGD peptide but also the sperm contain a large amount of sCS (Iwao 2014). Higher urodeles have developed sCS as a main soluble sperm factor for the entry of several sperm for physiological polyspermy, but the Ca2+ rise in response to the receptor-mediated signal has been almost abolished. In this connection, it is interesting to know the sperm factor in the primitive frog, Discoglossus pictus with large polyspermic eggs (Talevi & Campanella 1988, Talevi 1989).

We observe the divergence of sperm factors in tetrapod vertebrates from an evolutionary point of view. Although various factors appear to participate in egg activation during fish fertilization (Hart 1990, Iwamatsu 2000, Webb & Miller 2013), the eggs of primitive lamprey fish are activated without sperm entry (Kobayashi et al. 1994), indicating activation by the receptor-mediated sperm factor. The involvement of a soluble sperm factor has also been suggested in egg activation in bony fishes (Coward et al. 2003, 2005, Swann & Lai 2016). In an ancestor of tetrapod vertebrates, egg activation might have been caused by a dual system with both a receptor-mediated sperm factor and a soluble sperm factor. The primordial germ cells of urodeles are from mesodermic origins and are determined by response to extracellular signals like mammals (Porras-Gómez et al. 2021), suggesting that urodeles have retained an ancestral reproductive system during amniote evolution. An ancestor of amniotes could have been branched from anamniotes after the acquisition of sCS as a soluble sperm factor because sCS is necessary for egg activation in birds (Mizushima et al. 2014). In mammals, a receptor-mediated sperm factor to ensure a fast polyspermy block is probably no longer necessary, because a very small number of sperm reach the eggs in the fertilization site (La Spina et al. 2016, Muro et al. 2016). Instead, a potent soluble sperm factor, sperm-specific phospholipase Cζ (PLCζ), evolves for egg activation in amniotes (Coward et al. 2005, Mizushima et al. 2009, 2014, Swann & Lai 2016), accompanied by repetitive Ca2+ rises (Ca2+ oscillations) (Iwao 2012). A minor sperm factor of sCS (eCS) remains in mammalian sperm to support egg activation and prevent age-dependent male infertility (Kang et al. 2020). Thus, the dual system in egg activation might support the selection of a suitable system for each mode of fertilization in tetrapods to adapt to various reproductive conditions in terrestrial circumstances. The receptor-mediated sperm factor is suitable for egg activation and sperm-egg fusion to prevent polyspermy in the species exhibiting external fertilization in water, whereas the soluble sperm factor is appropriate for slow activation of large eggs, preserving nutrition and water for embryonic development in reptiles, birds, and the primitive mammal, platypus. To prove this hypothesis, further intensive investigation of sperm factors is required for various species of fishes, amphibians, reptiles, and lower mammals.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by JSPS KAKENHI Grant Number 19K06690 to Y I.

Author contribution statement

Y I conceived the outline of the review and wrote part of the paper. S U wrote part of the paper.

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    Ca2+ rises during egg activation in amphibians. (A) A Ca2+ wave in an egg of the monospermic anuran, Xenopus, showing the IS Ca2+ rise at the entry site of a single sperm followed by a Ca2+ wave spreading throughout the egg cytoplasm for 10–20 min after fertilization. (B) Multiple Ca2+ waves in an egg of the physiologically polyspermic urodele, Cynops, showing propagation of each Ca2+ wave preceded by a spike-like Ca2+ rise (Ca2+ spike) in approximately 25% of the egg cytoplasm for 30–40 min after fertilization.

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    A schematic model of a signaling cascade by the receptor-mediated sperm factor in egg activation of the monospermic anuran, Xenopus. Positively charged hemopexin domain of MMP-2 (MMP-2 HPX) on the sperm head binds to negatively charged ganglioside GM1 (GM1) on the microdomain (MD) in egg plasma membrane (PM), resulting in the activation of Src kinase (Src) to stimulate phospholipase C gamma (PLCG). Inositol 1, 4, 5-trisphosphate (IP3) produced by PLCG induces the IS Ca2+ rise through a cluster of IP3-receptors (IP3-R) in a patch of cortical ER (cER). MMP-2 HPX could bind integrins to transmit a signal for Ca2+ influx. IS Ca2+ rise induces Ca2+ release through cER to propagate a Ca2+ wave. In another case, a tryptic protease on the sperm colocalized with sperm-surface glycoprotein (SGP) and MMP-2 cleaves an egg receptor, Uroplakin III (UPIII) associated with UPIb, resulting in the activation of Src kinase. Phosphatidic acid (PA) produced by the activation of phospholipase D1b (PLD1b) may be involved in the activation of Src kinase.

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    A schematic model of a signaling cascade by the soluble sperm factor in egg activation of physiologically polyspermic urodele, Cynops. A sperm tryptic protease induces a spike-like Ca2+ rise (Ca2+ spike) via a putative PAR-like receptor on egg plasma membrane (PM). In addition, sperm-specific citrate synthase (sCS) is transferred from each sperm into the egg cytoplasm. (1) sCS may causes the Ca2+ release from the inner ER or from mitochondria by acetyl-CoA (aCoA) or oxaloacetate (OA). (2) sCS may stimulate ATP production to induce Ca2+ release through IP3-R. ER with IP3-R and PLCγ are concentrated along the astral microtubules in sperm asters to form a signal center of Ca2+ wave.

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