REVIEW

ComparativeBiology of CalciumSignalingduring
Fertilization andEggActivation in Animals
Stephen A. Stricker
1
Department of Biology, University of New Mexico, Albuquerque, New Mexico 87131
Duringanimal fertilizations, each oocyte or eggmust produce a proper intracellular calcium signal for development to
proceednormally. Asasupplement torecent synopsesof fertilization-inducedcalciumresponsesin mammals, thispaper
reviews thespatiotemporal properties of calciumsignalingduringfertilization andeggactivation in marineinvertebrates
andcompares thesepatterns with what has been reportedfor other animals. Basedon thecurrent database, fertilization
causesmost oocytesor eggstogeneratemultiplewavelikecalciumoscillationsthat ariseat least in part fromtherelease
of internal calciumstores sensitiveto inositol 1,4,5-trisphosphate(IP
3
). Such calciumwaves aremodulatedby upstream
pathwaysinvolvingoolemmal receptorsand/orsolublespermfactorsandinturnregulatecalcium-sensitivetargetsrequired
for subsequent development. Both protostome animals (e.g., mollusks, annelids, andarthropods) anddeuterostomes
(e.g., echinoderms and chordates) display fertilization-induced calcium waves, IP
3
-mediated calcium signaling, and the
ability to use a combination of external calcium inux and internal calcium release. Such ndings fail to support the
dichotomy in calciumsignalingmodes that hadpreviously been proposedfor protostomes vs deuterostomes andinstead
suggest that various features of fertilization-induced calcium signals are widely shared throughout the animal
kingdom. 1999Academic Press
Key Words: calciumwave;CICR;calciumoscillations;oocyte;meiosisarrest;maturation;spermfactor;ICSI;IP
3
;cADPr;
IP
3
R; RyR; capacitativecalciumentry; CaMKII; mouse; seaurchin; protostome; deuterostome.
INTRODUCTION
Duri ng ferti l i zati on, ani mal oocytes or eggs must undergo
a proper change i n thei r i ntracel l ul ar free cal ci um l evel s
([Ca
2
]
i
) to ensure that devel opment proceeds normal l y
(Epel , 1990; Nucci tel l i , 1991; Whi taker and Swann, 1993).
In the case of mammal s, the characteri sti c properti es of
ferti l i zati on-i nduced cal ci um si gnal i ng have been thor-
oughl y descri bed (Swann and Ozi l , 1994; Yanagi machi ,
1994; Mi yazaki , 1995; Schul tz and Kopf, 1995; Kl i ne, 1996;
BenYosef and Shal gi , 1998; Ozi l , 1998). However, to gai n a
broader perspecti ve, thi s revi ew compares the spati otempo-
ral patterns of cal ci um si gnal s duri ng normal ferti l i zati on or
arti ci al acti vati on i n mari ne i nvertebrates where cal ci um
l evel s have been di rectl y moni tored i n oocytes or eggs (i .e.,
i n femal e gametes before or after the compl eti on of mei oti c
maturati on). In addi ti on, the contri buti ons of external cal -
ci um i nux and i nternal cal ci um rel ease are assessed i n
order to reeval uate the hypothesi s that i n ani mal s i n whi ch
the adul t mouth devel ops from the embryoni c bl astopore
(i .e., protostomes ) fundamental l y di fferent mechani sms
of generati ng cal ci um transi ents are empl oyed duri ng fer-
ti l i zati on than are used i n deuterostomes, whi ch do not
deri ve thei r mouth from the bl astopore (Jaffe, 1983, 1985).
The group-by-group synopsi s i s organi zed accordi ng to a
tradi ti onal phyl ogeny of i nvertebrates (Pearse et al., 1987)
and i s subsequentl y synthesi zed wi th representati ve data
obtai ned from other ani mal s wi th the ai m of addressi ng a
key questi on i n devel opmental bi ol ogy: namel y, what ki nds
of cal ci um si gnal s are used by ani mal oocytes and eggs to
tri gger normal devel opment?
CNIDARIA
Duri ng ferti l i zati on i n hydrozoan jel l ysh (Phyl um Cni -
dari a, Cl ass Hydrozoa), the egg generates a si ngl e cal ci um
transi ent of undetermi ned spati al properti es (Freeman and
Ri dgway, 1993) (Tabl e 1; Fi g. 1A). Al though the sources of
cal ci um mobi l i zed duri ng ferti l i zati on have not been di -
1
Fax: (505) 277-0304. E-mai l : sstr@unm.edu.
Devel opmental Bi ol ogy 211, 157176 (1999)
Arti cl e ID dbi o.1999.9340, avai l abl e onl i ne at http://www.i deal i brary.com on
0012-1606/99 $30.00
Copyri ght 1999 by Academi c Press
Al l ri ghts of reproducti on i n any form reserved. 157
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c
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158 Stephen A. Stricker
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
rectl y eval uated, cal ci um rel ease from i nternal stores may
pl ay a rol e, si nce cal ci um i onophore can tri gger a cal ci um
transi ent i n unferti l i zed eggs i ncubated i n cal ci um-free
seawater (CaFSW) (Freeman and Ri dgway, 1987). Moreover,
the mature eggs of cni dari ans exhi bi t a cal ci um transi ent
when i njected wi th i nosi tol 1,4,5-tri sphosphate (IP
3
) (Free-
man and Ri dgway, 1991) but not when treated wi th excess
potassi um (Freeman and Ri dgway, 1993), whi ch sti mul ates
external cal ci um i nux through vol tage-gated cal ci um
channel s i n the pl asmal emma (Conl ey and Brammer, 1998).
FIG. 1. Temporal patterns of ferti l i zati on-i nduced cal ci um si gnal s i n protostome (BF) vs deuterostome (GL) ani mal s [note: cni dari ans
(A) are not readi l y al l i ed wi th ei ther l i neage (Pearse et al., 1987)]. Normal state of oocyte maturati on at ferti l i zati on: prophase I-arrested (D,
F); between germi nal vesi cl e breakdown and pol ar body formati on (H); metaphase I-arrested (B, C, E, I); metaphase II-arrested (JL);
pronucl ear egg (A, G). Ampl i tudes, durati ons, and frequenci es of cal ci um transi ents are not drawn to scal e, and the ti mi ngs of rst cel l cycl e
events are onl y approxi mate (for perti nent data, see Tabl e 1 and text). Cal ci um traces and cel l cycl e chronol ogy are based on (A) Freeman
and Ri dgway (1991, 1993); (B) Stri cker (1996b); (C) Togo et al. (1993), Deguchi and Osanai (1994b); (D) Gei l enki rchen et al. (1977), Deguchi
and Osanai (1994a); (E) Harvey (1939), Eckberg and Mi l l er (1995); (F) Goul d and Stephano (1996), Stephano and Goul d (1997); (G) Shen and
Buck (1993), Wi l di ng et al. (1996); (H) Stri cker (1995); (I) Speksni jder et al. (1989), McDougal l and Levasseur (1998); (J) Ri dgway et al. (1977),
Fl uck et al. (1991), Abraham et al. (1993) for the medaka Oryzias (whi ch forms the second pol ar body 15 mi n postferti l i zati on and
generates sl ow cal ci um waves al ong the cl eavage furrow pri or to rst cl eavage at 90 mi n postferti l i zati on), Creton et al. (1998) for the
zebrash Danio (whi ch undergoes rst cl eavage 45 mi n postferti l i zati on); (K) Busa and Nucci tel l i (1985), Keati ng et al. (1994); and (L)
Tombes et al. (1992), Jones et al. (1995a) for the mouse Mus.
159 Fertilization-I nduced Ca
2
Signals
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
FIG. 2. Spati al properti es of ferti l i zati on-i nduced cal ci um si gnal s i n protostomes (nemertean worms: AE) vs deuterostomes (starsh: F,
G), showi ng pseudocol ored i mages (AC, F, G) of rati oed confocal data from Cal ci um Green-l oaded speci mens exami ned every 5 s. Bl ues
encode l ow cal ci um l evel s, whereas yel l ows and reds correspond to hi gher cal ci um l evel s. (A) Two mature oocytes from the nemertean
Micrura alaskensis. A synchronousl y propagated corti cal ash (arrowheads) ari ses from external cal ci um i nux at the onset of
ferti l i zati on i n each oocyte. Fi rst frame i s before sperm addi ti on; second frame i s at 105 s after sperm addi ti on, and each subsequent frame
of the 11-frame sequence i s taken at 5-s i nterval s. (B) Two ferti l i zati on-i nduced cal ci um waves (arrows) ari si ng 5 and 10 mi n after
i nsemi nati on i n the M. alaskensisoocyte previ ousl y shown generati ng a corti cal ash i n the top row of A. (C)Ferti l i zati on-i nduced cal ci um
transi ents i n an i mmature oocyte (top two rows) and a mature oocyte (bottom row) of the nemertean Cerebratulus lacteus. Note the
non-wavel i ke propagati on patterns (arrowheads)i n the i mmature oocyte vs the poi nt-source cal ci um wave (arrow)i n the mature speci men.
160 Stephen A. Stricker
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
Thus, ferti l i zati on may i nvol ve cal ci um rel ease modul ated
by IP
3
receptors (IP
3
Rs) (Berri dge, 1993; Bezprozvanny and
Ehrl i ch, 1995), whi ch presumabl y occur mai nl y on the eggs
endopl asmi c reti cul um (ER) (Han and Nucci tel l i , 1990).
However, i t remai ns to be determi ned (i ) i f the ER of cni -
dari an eggs al so contai ns functi onal ryanodi ne receptors
(RyRs) (Sorrenti no, 1996), the second major cl ass of cal -
ci um channel receptors used by cel l s to mobi l i ze i nternal
cal ci um stores (Tabl e 2); and (i i ) whether ei ther or both of
these receptor types actual l y contri bute to a normal ferti l -
i zati on response.
NEMERTEA
Ful l y grown oocytes of the nemertean worm Cerebratu-
lus arrest at metaphase I and upon i nsemi nati on generate
mul ti pl e cal ci um transi ents for 75 mi n (Stri cker, 1996b;
Fi g. 1B). The rst ferti l i zati on-i nduced cal ci um transi ent
compri ses an essenti al l y synchronous corti cal ash that
i s mi mi cked by excess potassi um or el i mi nated by the
cal ci um channel bl ocker cobal t chl ori de, col l ecti vel y sug-
gesti ng a dependence on external cal ci um i nux (Stri cker,
1996b). After the corti cal ash, ferti l i zed oocytes produce
10 cal ci um waves that i ni ti al l y ari se near the sperm entry
si te (Stri cker, 1996b). Subsequentl y, the waves tend to
ori gi nate from the vegetal hemi sphere and do not requi re
external cal ci um, si nce they persi st i n CaFSW (Stri cker,
1996b). Al though unferti l i zed oocytes can mobi l i ze cal ci um
when treated wi th ryanodi ne to sti mul ate RyRs, ferti l i zati on-
i nduced cal ci um waves appear to depend on IP
3
-medi ated
cal ci um rel ease, gi ven that they are di srupted by hepari n
(Stri cker, 1996b), whi ch i s a somewhat sel ecti ve i nhi bi tor of
IP
3
Rs (Hi l l et al., 1987).
A corti cal ash and wavel i ke osci l l ati ons al so occur
when mature oocytes of other nemertean speci es are ferti l -
i zed (Fi gs. 2A and 2B). By contrast, prophase-arrested i mma-
ture oocytes of Cerebratulus remai n uncl eaved after sperm
addi ti on and generate l ow-ampl i tude, non-wavel i ke cal -
ci um transi ents for onl y 25 mi n, presumabl y because the
oocytes ER had not ful l y matured before i nsemi nati on
(Stri cker et al., 1998) (Fi gs. 2C2E).
MOLLUSCA
Oocytes produced by cl ams and thei r al l i es (Phyl um
Mol l usca, Cl ass Bi val vi a) arrest at ei ther prophase I or
metaphase I and typi cal l y undergo 515 cal ci um transi ents
after i nsemi nati on (Deguchi and Osanai , 1994b; Fi g. 1C),
al though ferti l i zed oocytes of the bi val ve Mactra di spl ay
onl y a si ngl e cal ci um transi ent fol l owed by an el evated
pl ateau (Deguchi and Osanai , 1994a; Fi g. 1D). The i ni ti al
ferti l i zati on-i nduced cal ci um transi ent of Ruditapes and
Mytilus ari ses synchronousl y around the oocyte as a corti -
cal ash that l acks a poi nt-source ori gi n (Abdel maji d et al.,
1993; Deguchi and Osanai , 1994b). In Mytilus, the corti cal
ash i s el i mi nated by the cal ci um channel bl ocker me-
thoxyverapami l , i ndi cati ng that external cal ci um i nux
occurs at the onset of ferti l i zati on (Deguchi et al., 1996).
Conversel y, subsequent cal ci um osci l l ati ons generated i n
Mytlius oocytes conti nue to occur i n the presence of
methoxyverapami l (Deguchi et al., 1996) or after transfer to
CaFSW (Deguchi and Osanai , 1994b), and such postash
osci l l ati ons are bl ocked i n hepari n-l oaded oocytes, suggest-
i ng a l ater dependence on IP
3
-medi ated cal ci um rel ease
(Deguchi and Osanai , 1994a; Deguchi et al., 1996). More-
over, the cal ci um osci l l ati ons that fol l ow the i ni ti al corti cal
ash propagate as di sti nct waves, rather than as synchro-
nous el evati ons (Deguchi and Mori sawa, 1997).
Prophase-arrested oocytes of several bi val ve speci es gen-
erate at l east one cal ci um transi ent and/or undergo germi -
nal vesi cl e breakdown (GVBD) when treated wi th acti vat-
i ng agents (Deguchi and Osanai , 1995; Li ppai et al., 1995;
Fong et al., 1997). External cal ci um i nux i s apparentl y
i nvol ved i n such acti vati ons, si nce (i ) GVBD i s preceded by
cal ci um i nux and prevented by cal ci um i nux bl ockers
(Dube and Guerri er, 1982; Kadam et al., 1990; Juneja et al.,
1994; Juneja and Koi de, 1996); (i i ) cal ci um i onophore tri g-
gers GVBD i n Spisula oocytes i ncubated i n cal ci um-
contai ni ng seawater but not i n CaFSW (Schuetz, 1975;
Kadam et al., 1990); and (i i i ) the pre-GVBD cal ci um ri se
i nduced by the hormone serotoni n often requi res external
cal ci um to be ful l y effecti ve (Deguchi and Osanai , 1995).
Si mi l arl y, cal ci um i nux seems to be i nvol ved i n opti mal l y
acti vati ng metaphase I-arrested oocytes of Mytilus, si nce
(D, E) Two sets of compressed confocal z seri es of a C. lacteus oocyte i njected wi th the vi tal ER i ndi cator Di I, showi ng the formati on of
ER mi crodomai ns (arrows) that may pl ay a rol e i n produci ng a normal cal ci um response (D, 75 mi n postremoval from the ovary; E, 165
mi n postremoval from ovary). (F)Oocyte from the starsh Pisaster ochraceus, showi ng a normal ferti l i zati on-i nduced cal ci um wave (arrow)
i n the presence of the cal ci um channel bl ocker ni fedi pi ne. Note the concave nature of the wavefront, whi ch i ndi cates a more rapi d
transmi ssi on around the peri phery than through the center of the oocyte (i .e., even though the peri pheral pathway represents a greater
di stance than di rectl y through the center of the oocyte, the cal ci um wave advances around the cortex of the oocyte before ful l y traversi ng
the central oopl asm). (G) A 3-D cyl i ndri cal reconstructi on of a ti me-l apse confocal data set showi ng ferti l i zati on i n a Pisaster oocyte. For
such reconstructi ons, the ci rcul ar opti cal secti ons i n a ti me-l apse confocal data set were stacked on top of each other so that the verti cal
axi s equal s ti me, and the top of the rendered cyl i nder represents the oocyte before i nsemi nati on (Stri cker, 1994); verti cal scal e bar, 200 s.
The ri ght-hand rectangl e i s the cl eaved cyl i nder to depi ct the progressi on of the ferti l i zati on-i nduced cal ci um wave wi thi n the oocyte
(arrow). Note that compared to the oocyte center, the wave travel s more rapi dl y i n the cortex, judgi ng from the shal l ower sl ope of the
wavefront (i .e., l ess ti me el apses duri ng si mi l ar di stances travel ed i n the cortex vs center). (AC) Stri cker, unpubl i shed observati ons; (D, E)
Stri cker et al. (1998); (F, G) Stri cker et al. (1994). Hori zontal scal e bar, 50 m.
161 Fertilization-I nduced Ca
2
Signals
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
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162 Stephen A. Stricker
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
ei ther a rapi d repl acement of hi gh-potassi um seawater wi th
CaFSW (Deguchi and Osanai , 1994b) or an i ncubati on i n
cal ci um i nux bl ockers before the potassi um treatment
(Kranti c and Ri vai l l er, 1996) si gni cantl y reduces the num-
ber of oocytes formi ng pol ar bodi es.
Neverthel ess, i nternal cal ci um rel ease may al so occur
duri ng acti vati on of several bi val ves exami ned, gi ven that
(i ) vari ous agoni sts can tri gger cal ci um transi ents and at
l east some GVBD i n CaFSW (Guerri er et al., 1993; Gobet et
al., 1995; Li ppai et al., 1995); (i i ) IP
3
i s capabl e of el i ci ti ng
GVBD (Bl oom et al., 1988; Guerri er et al., 1996); and (i i i )
serotoni n, whi ch normal l y i nduces a transi ent ri se i n IP
3
l evel s pri or to GVBD (Gobet et al., 1994), fai l s to cause
GVBD i n hepari n-l oaded speci mens (Deguchi and Osanai ,
1995).
ANNELIDA
Ferti l i zati on causes metaphase I-arrested oocytes of the
annel i dan worm Chaetopterus to undergo 327 cal ci um
transi ents that cease by 10 mi n posti nsemi nati on (Eck-
berg and Mi l l er, 1995; Fi g. 1E). The rst cal ci um transi ent
fai l s to propagate compl etel y across the oopl asm and i s
fol l owed by mul ti pl e ful l y propagated cal ci um waves that
eventual l y ari se from a repeated pacemaker si te (Eckberg
and Mi l l er, 1995). Al though the sources of cal ci um mobi -
l i zed duri ng ferti l i zati on have not been di rectl y anal yzed,
prophase-arrested oocytes of Chaetopterus (Ikegami et al.,
1976) and Pectinaria (Anstrom and Summers, 1981) typi -
cal l y requi re external cal ci um to mature properl y. Si mi -
l arl y, when treated wi th excess potassi um, metaphase-
arrested Chaetopterus speci mens produce cal ci um waves
l i ke those of ferti l i zati on (Eckberg and Mi l l er, 1995), col l ec-
ti vel y suggesti ng that acti vati on depends on external cal -
ci um. However, other ndi ngs i mpl i cate i nternal sources of
cal ci um, si nce hi gh concentrati ons of cal ci um i onophore
acti vate Chaetopterus oocytes i n CaFSW (Eckberg and
Carrol l , 1982), and the appl i cati on of CaMg-free seawater by
i tsel f l eads to GVBD i n Sabellaria (Peucel l i er, 1977). More-
over, homogenates of Chaetopterus oocytes mobi l i ze cal -
ci um i n response to ei ther IP
3
or the thi ol reagent thi mero-
sal (Thomas et al., 1998), whi ch i n other cel l s tends to
sensi ti ze IP
3
Rs (Mi yazaki et al., 1992a)but may al so rel ease
cal ci um through RyRs i n some cases (McDougal l et al.,
1993).
ECHIURA
Fol l owi ng i nsemi nati on, prophase-arrested oocytes of the
echi uran worm Urechis generate a cal ci um transi ent that
does not form a di sti nct poi nt-source wave (Stephano and
Goul d, 1997). The i ni ti al cal ci um transi ent i s fol l owed by a
pl ateau of el evated cal ci um (Fi g. 1F) that can cul mi nate i n
parti cul arl y hi gh nucl ear cal ci um l evel s, and hal f of the
ferti l i zed oocytes al so exhi bi t at l east one more cal ci um ri se
that propagates i n a non-wavel i ke fashi on (Stephano and
Goul d, 1997).
The ferti l i zati on-i nduced cal ci um response of Urechis
i nvol ves cal ci um i nux, based on (i )
45
Ca measurements
(Johnston and Paul , 1977); (i i ) al terati on of ferti l i zati on-
i nduced cal ci um dynami cs by perfusi ons of seawater con-
tai ni ng the cal ci um chel ati ng agent BAPTA (Stephano and
Goul d, 1997); and (i i i ) dupl i cati on of the cal ci um response
i n the absence of sperm by openi ng ool emmal cal ci um
channel s (Stephano and Goul d, 1997). Accordi ngl y, treati ng
unferti l i zed oocytes wi th exogenous trypsi n (Johnston and
Paul , 1977) or the P23 pepti de from sperm acrosomes
(Stephano and Goul d, 1997) el i ci ts ferti l i zati on-l i ke cal -
ci um dynami cs and/or acti vati on, provi ded that external
cal ci um i nux i s al l owed to occur (Stephano and Goul d,
1997). Unferti l i zed oocytes can al so mobi l i ze i nternal cal -
ci um stores i n response to IP
3
, but such treatments do not
ful l y mi mi c the ferti l i zati on response or tri gger acti vati on
(Stephano and Goul d, 1997). Col l ecti vel y, such data reveal a
need for external cal ci um i nux duri ng ferti l i zati on, al -
though a suppl ementati on by i nternal cal ci um rel ease can-
not be rul ed out (Stephano and Goul d, 1997).
ARTHROPODA
In the shri mp Sicyonia (Phyl um Arthropoda, Subphyl um
Crustacea), magnesi um i ons i n the seawater acti vate meta-
phase I-arrested oocytes by causi ng an i ntracel l ul ar cal ci um
wave i n these speci mens (Li ndsay et al., 1992). A si mi l ar
cal ci um wave i s i nduced by ei ther Mg
2
i n the absence of
external cal ci um or cal ci um i onophore treatments i n Mg-
FSW (Li ndsay et al., 1992). Moreover, the Mg
2
-i nduced
Ca
2
wave i s mi mi cked by IP
3
i njecti ons and bl ocked by
tyrosi ne ki nase i nhi bi tors, suggesti ng the i nvol vement of
an IP
3
-dependent rel ease of i nternal cal ci um stores regu-
l ated by a tyrosi ne ki nase-based si gnal i ng pathway (Li ndsay
and Cl ark, 1994). In the presence of sperm, acti vated oo-
cytes i nvari abl y generate a second cal ci um transi ent whi ch
may represent a ferti l i zati on-i nduced cal ci um response,
al though thi s remai ns to be veri ed (Li ndsay et al., 1992).
Magnesi um i ons al so acti vate unferti l i zed oocytes of the
prawn Palaemon by tri ggeri ng a seri es of IP
3
-medi ated
cal ci um osci l l ati ons that l ast for 76 5.5 mi n, fol l owed by
a 49.6 4.5-mi n postosci l l atory pl ateau of el evated cal ci um
that rel i es on external cal ci um i nux (Goudeau and
Goudeau, 1996, 1998). Whether any of these cal ci um tran-
si ents propagate as waves has not been establ i shed. More-
over, as i n Sicyonia, the type of cal ci um response normal l y
el i ci ted by ferti l i zati on remai ns uncl ear.
ECHINODERMATA
Echinoidea
Duri ng ferti l i zati on, eggs of sea urchi ns and other echi -
noi ds (Phyl um Echi nodermata, Cl ass Echi noi dea)generate a
si ngl e 5- to 10-mi n cal ci um transi ent that spreads as a
wave across the oopl asm (Stei nhardt et al., 1977; Gi l l ot and
Whi taker, 1993; Tabl e 1). In Lytechinus, the ferti l i zati on-
163 Fertilization-I nduced Ca
2
Signals
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
i nduced cal ci um wave i s di rectl y preceded by an i nux of
cal ci um l eadi ng to a corti cal ash that i s not requi red for
normal wave producti on (McDougal l et al., 1993; Shen and
Buck, 1993). The cal ci um wave i s then fol l owed by a few
postferti l i zati on cal ci um transi ents (Stei nhardt, 1990;
Browne et al., 1996; Fi g. 1G).
Al though external cal ci um i nux occurs at the onset of
sea urchi n ferti l i zati on (Paul and Johnston, 1978), normal
ferti l i zati ons can sti l l be achi eved i n CaFSW usi ng prere-
acted sperm (Schmi dt et al., 1982; McDougal l et al., 1993).
Accordi ngl y, unferti l i zed sea urchi n eggs are acti vated by
cal ci um i onophore i n CaFSW (Stei nhardt and Epel , 1974)
but not by excess potassi um i n cal ci um-contai ni ng seawa-
ter (Schmi dt et al., 1982), suggesti ng that cal ci um i nux i s
not a major dri vi ng force i n acti vati on. Conversel y, ferti l i -
zati on can be i nhi bi ted by pretreatments wi th l anthanum
or cal ci um chel ators to bl ock cal ci um i nux (Creton and
Jaffe, 1995), i ndi cati ng that cal ci um i nux may i ndeed pl ay
a necessary rol e (for a di scussi on of the di screpanci es, see
Jaffe, 1990; Creton and Jaffe, 1995; Jones et al., 1998b).
As poi nted out i n previ ous revi ews (Whi taker and Swann,
1993; Shen, 1995), unferti l i zed sea urchi n eggs can rel ease
i nternal cal ci um stores vi a IP
3
- or non-IP
3
-medi ated mecha-
ni sms. Fol l owi ng i nsemi nati on, a cal ci um wave occurs i n
the presence of i nhi bi tors agai nst IP
3
Rs or RyRs but not
when both i nhi bi tor types are used, suggesti ng that the two
receptors functi on redundantl y duri ng ferti l i zati on (Gal i one
et al., 1993; Lee et al., 1993). However, i t was not reported
i f the speci mens di spl ayi ng cal ci um waves underwent nor-
mal cl eavage, and other anal yses i ndi cate that ferti l i zati on
may actual l y requi re IP
3
-medi ated cal ci um rel ease (Mohri
et al., 1995; Lee et al., 1996; Lee and Shen, 1998; Carrol l et
al., 1999), whi ch i n turn depends on functi onal phospho-
l i pase C

(PLC

) (Carrol l et al., 1999). Thus, i t remai ns

uncl ear i f sea urchi n RyRs can ful l y substi tute for IP
3
Rs
duri ng normal devel opment.
Asteroidea
Prophase-arrested oocytes of starsh (Phyl um Echi noder-
mata, Cl ass Asteroi dea) undergo GVBD i n response to the
hormone 1-methyl adeni ne and proceed through mei osi s
wi thout arrest (Mei jer and Guerri er, 1984). Duri ng ferti l i -
zati on i n Pisaster and other starsh, maturi ng oocytes
produce a si ngl e wavel i ke cal ci um transi ent that mai ntai ns
el evated [Ca
2
]
i
for 1030 mi n (Ei sen and Reynol ds, 1984;
Stri cker et al., 1994). The wave may (Carrol l et al., 1997) or
may not (Stri cker et al., 1994)fol l ow a di sti nct corti cal ash
and i s general l y compl eted about an hour before the onset of
some postferti l i zati on cal ci um osci l l ati ons (Stri cker, 1995;
Fi g. 1H).
External cal ci um i nux does not appear to be requi red for
the producti on of a cal ci um wave, si nce unferti l i zed oo-
cytes can be acti vated by cal ci um i onophore i n CaFSW
(Stei nhardt et al., 1974), and a normal -appeari ng wave
conti nues to be generated when oocytes are ferti l i zed i n the
presence of the cal ci um channel bl ock er ni fedi pi ne
(Stri cker et al., 1994) (Fi g. 2F). As further evi dence for i n-
ternal cal ci um rel ease, unferti l i zed oocytes are capabl e of
generati ng cal ci um transi ents i n response to ei ther IP
3
or
agents such as ryanodi ne, caffei ne, and cycl i c ADP-ri bose
(cADPr)that target RyRs (Stri cker, 1995; Santel l a, 1996). In
prophase-arrested speci mens of Asterina pectinifera, both
IP
3
- and non-IP
3
-medi ated cal ci um rel ease can yi el d a cal -
ci um ux i n the cytopl asm and nucl eus, and the nucl ear
cal ci um el evati on i n parti cul ar appears to pl ay an i mportant
rol e i n GVBD, based on i njecti ons of agoni sts or BAPTA
(Santel l a and Kyozuka, 1994, 1997). However, duri ng ferti l -
i zati ons of post-GVBD speci mens i n other starsh speci es,
cal ci um seems to be mobi l i zed predomi nantl y through
IP
3
Rs, gi ven that (i ) pretreatment wi th hepari n i nhi bi ts
cl eavage and causes aberrant cal ci um dynami cs (Stri cker,
1995); and (i i ) ferti l i zati on-i nduced cal ci um waves and
cl eavage are el i mi nated by prei njecti ons of recombi nant
src-homol ogy 2 (SH2) domai ns of PLC

, whi ch bl ock IP
3
-
medi ated cal ci um rel ease regul ated by tyrosi ne ki nases
(Carrol l et al., 1997).
CHORDATA
Urochordata
Duri ng ferti l i zati on, metaphase I-arrested oocytes of as-
ci di ans (Phyl um Chordata, Subphyl um Urochordata, Cl ass
Asci di acea) generate mul ti pl e cal ci um waves whi l e com-
pl eti ng mei osi s (Speksni jder et al., 1989; McDougal l and
Sardet, 1995; Sardet et al., 1998; Fi g. 1I). In Phallusia and
other speci es, the rst ferti l i zati on-i nduced cal ci um tran-
si ent, or acti vati on wave (Speksni jder, 1990a), ori gi nates
from the poi nt of sperm entry and di rectl y precedes a
mi crol ament-medi ated corti cal contracti on (Speksni jder
et al., 1990a,b,c; McDougal l and Sardet, 1995; Roegi ers et
al., 1996). Subsequentl y, each ferti l i zed oocyte produces
about one to two dozen cal ci um waves that shi ft thei r onset
si te toward the vegetal pol e, where they eventual l y ori gi -
nate from an ER-ri ch vegetal pacemaker whi l e di spl ayi ng a
more corti cal l y enhanced propagati on (Speksni jder, 1992;
McDougal l and Sardet, 1995).
Ferti l i zati ons of Phallusia oocytes i n CaFSW can yi el d
normal cal ci um dynami cs and devel opment (Speksni jder et
al., 1989). Accordi ngl y, i onophore treatments of unferti l -
i zed oocytes i n CaFSW el i ci t corti cal contracti ons and pol ar
body formati on (McDougal l et al., 1995), suggesti ng that
the cal ci um mobi l i zed duri ng ferti l i zati on comes from i n-
ternal stores. However, i n other studi es of Phallusia, re-
moval of external cal ci um causes aberrant ferti l i zati on po-
tenti al s and i ncreased pol yspermy, whi ch can be prevented
by a pul se of normal seawater at the onset of ferti l i zati on
(Goudeau and Goudeau, 1993). Si mi l arl y, Ciona oocytes
ferti l i zed i n CaFSW fai l to produce ei ther the l ater-oc-
curri ng cal ci um osci l l ati ons of normal ferti l i zati ons or a
second pol ar body (Sensui and Mori sawa, 1996), col l ecti vel y
suggesti ng that devel opment requi res an i nux of cal ci um.
An IP
3
-medi ated pathway i s apparentl y uti l i zed duri ng
ferti l i zati on, gi ven that hepari n or an anti body agai nst
IP
3
Rs di srupts ferti l i zati on-i nduced cal ci um osci l l ati ons i n
164 Stephen A. Stricker
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
Ciona, whereas rutheni um red, whi ch can be used to
i nhi bi t RyRs rather than IP
3
Rs, has no noti ceabl e effect
(Russo et al., 1996; Yoshi da et al., 1998). Si mi l arl y, unfer-
ti l i zed oocytes of Ciona or Phallusia generate ferti l i zati on-
l i ke cal ci um osci l l ati ons and form pol ar bodi es when sub-
jected to (i ) adenophosti n, a potent agoni st of IP
3
Rs; (i i )
conti nuousl y perfused IP
3
; or (i i i ) mul ti pl e IP
3
pul ses (Mc-
Dougal l and Sardet, 1995; Al bri eux et al., 1998; Yoshi da et
al., 1998). Conversel y, treatments wi th ryanodi ne, cADPr,
caffei ne, or ni coti ni c aci dadeni ne di nucl eoti de phosphate
(NAADP) to sti mul ate non-IP
3
-based si gnal i ng pathways
fai l to tri gger a marked cal ci um response or ful l acti vati on
(McDougal l and Sardet, 1995; Al bri eux et al., 1997, 1998;
Wi l di ng et al., 1998).
However, contri buti ons from non-IP
3
-medi ated cal ci um
rel ease cannot be rul ed out for Ciona or Phallusia, gi ven
that (i ) hepari n-l oaded oocytes di spl ay one to a few cal ci um
transi ents after ferti l i zati on or sperm extract i njecti ons
(Russo et al., 1996; Wi l di ng and Dal e, 1998); and (i i ) a
si gnal i ng pathway tri ggered by ni tri c oxi de can cause a
cal ci um ux apparentl y vi a receptors other than IP
3
Rs
(Grumetto et al., 1997; Wi l di ng et al., 1998). Moreover,
non-IP
3
receptors may contri bute to hi ghl y l ocal i zed and/or
ephemeral cal ci um transi ents, whi ch are not easi l y de-
tected but are neverthel ess needed for regul ati ng ool emmal
capaci tance and currents (Al bri eux et al., 1997, 1998; Wi l d-
i ng et al., 1998).
CALCIUM WAVES DURING
FERTILIZATION IN DEUTEROSTOMES
AND PROTOSTOMES
L. F. Jaffe (1983, 1985) hypothesi zed that deuterostome
ani mal s rel ease i nternal stores of cal ci um to generate cal -
ci um waves duri ng ferti l i zati on, whereas the ferti l i zed
oocytes of protostomes uti l i ze external cal ci um i nux to
produce non-wavel i ke cal ci um transi ents. However, as
summari zed i n Tabl e 1, poi nt-source cal ci um waves oc-
cur not onl y i n deuterostomes but al so duri ng ferti l i zati on
(Eckberg and Mi l l er, 1995; Stri cker, 1996b; Deguchi and
Mori sawa, 1997) or oocyte acti vati on (Li ndsay et al., 1992)
i n several phyl a that are general l y bel i eved to represent
protostome l i neages, based on both cl assi cal embryol ogi cal
cri teri a [Pearse et al., 1987; Gi l bert, 1994al though see
Hertzl er and Cl ark (1992) for an al ternati ve i nterpretati on
of Sicyonias ontogeny] and mol ecul ar-based phyl ogeni es
(Agui nal do and Lake, 1998; Wi nnepenni nckx et al., 1998).
Even i n mammal s where some synchronousl y propagated
cal ci um uxes can occur duri ng maturati on or l ate ferti l i -
zati on (Carrol l et al., 1994; Shi rai shi et al., 1995), the i ni ti al
ferti l i zati on-i nduced cal ci um transi ents are wavel i ke (Fuji -
wara et al., 1993; Wu et al., 1996), and currentl y onl y
echi uran protostomes have been shown to l ack cal ci um
waves (Stephano and Goul d, 1997).
The mean vel oci ti es of ferti l i zati on-i nduced cal ci um
waves fal l wi thi n a rel ati vel y narrow range of 1030
m/s, whi ch i s consi stent wi th a fundamental l y conserved
reacti on-di ffusi on-based mechani sm of wave propagati on
(Jaffe, 1991, 1995). As di ffusi bl e messengers for propagati ng
such gl obal cal ci um waves, oocytes may use IP
3
(Al l bri tton
et al., 1992) or cal ci um i ons that promote a cal ci um-
i nduced cal ci um rel ease (CICR) acti ng on RyRs (Gal i one
and Summerhi l l , 1996) and/or IP
3
Rs (Gal i one et al., 1993;
Whi taker and Swann, 1993). In some speci es (Mohri and
Hamaguchi , 1991; Stri cker et al., 1994; Fontani l l a and Nuc-
ci tel l i , 1998), the cal ci um wave travel s faster around the
cortex than through the central oopl asm and thus di spl ays
a concave wavefront (Fi gs. 2F and 2G). Such di fferences i n
transmi ssi on rates may be due to an enhanced di stri buti on
of peri pheral ER structures (McPherson et al., 1992; Mehl -
mann et al., 1995; Stri cker et al., 1998; Fi ssore et al., 1999)
and/or a gradi ent of IP
3
concentrati ons (Wagner et al., 1998).
SINGLE VS MULTIPLE CALCIUM
TRANSIENTS FOLLOWING
FERTILIZATION
Ferti l i zati on i n most ani mal s, i ncl udi ng numerous mam-
mal s exami ned, resul ts i n mul ti pl e cal ci um transi ents
(Tabl e 1). Such osci l l atory changes i n free cal ci um are
general l y bel i eved to ari se from i nteracti ons between two
separate pool s of bound cal ci um (Berri dge, 1991)or from the
bi phasi c rel ease of cal ci um wi thi n a si ngl e pool that i s
di fferenti al l y regul ated by such modul ators as IP
3
and
cal ci um (De Young and Kei zer, 1992).
The common occurrence of ferti l i zati on-i nduced cal ci um
osci l l ati ons may si mpl y reect the need for a l ong-term
cal ci um response wi thout the conti nuous el evati on of cal -
ci um that can be toxi c to cel l s (Dowd, 1995). On the other
hand, an osci l l atory response coul d provi de an i nherentl y
more robust tri gger of cel l ul ar processes, si nce i t carri es not
onl y the ampl i tude-rel ated si gnal that accompani es a sol i -
tary cal ci um pul se but al so frequency-encoded i nforma-
ti on (Gu and Spi tzer, 1995; Tang and Othmer, 1995). Ac-
cordi ngl y, mammal s can di spl ay speci es-speci c di fferences
i n the frequenci es of thei r ferti l i zati on-i nduced cal ci um
osci l l ati ons (Wu et al., 1997; Jones, 1998), and a si ngl e
cal ci um pul se often fai l s to acti vate ani mal oocytes ful l y,
whereas mul ti pl e cal ci um transi ents successful l y rel ease
oocytes from mei oti c arrest to form both pol ar bodi es
(Deguchi and Osani , 1995; Stri cker, 1996b; Al bri eux 1997;
Lawrence et al., 1998; Ozi l , 1998).
The questi on then ari ses: why do cni dari ans, echi no-
derms, sh, and frogs generate a sol i tary cal ci um transi ent
at ferti l i zati on (Fi gs. 1A, 1G, 1H, 1J, and 1K)? In cases where
mei osi s ei ther ful l y precedes ferti l i zati on (sea urchi ns and
cni dari ans) or l acks a natural arrest poi nt once GVBD has
been tri ggered (starsh), a sol i tary ferti l i zati on-i nduced
transi ent may be sufci ent, gi ven that a resumpti on from
mei oti c arrest i s not requi red. Al ternati vel y, unl i ke the
many hours that el apse between mei oti c resumpti on and
i nterphase i n mammal i an zygotes (Jones, 1998; Fi g. 1L),
ferti l i zati on i n sh (Iwamatsu and Ohta, 1978) and frogs
(Rugh, 1951) can tri gger a rapi d (1030 mi n) transi ti on
165 Fertilization-I nduced Ca
2
Signals
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
from MII arrest to pronucl ear formati on pri or to rst cl eav-
age. Accordi ngl y, the abbrevi ated nature of the postferti l -
i zati on phase i n these zygotes coul d obvi ate the need for a
repeated seri es of cal ci um transi ents such as found i n mam-
mal s (Jones, 1998).
EXTERNAL CALCIUM INFLUX VS
INTERNAL CALCIUM RELEASE DURING
FERTILIZATION
The current database suggests that a ferti l i zati on-i nduced
i nux of external cal ci um i s not restri cted to protostomes
as postul ated by Jaffe (1983, 1985) but functi ons al ong wi th
i nternal cal ci um rel ease throughout the ani mal ki ngdom
(Tabl e 2). Even i n mammal i an oocytes that can be acti vated
by an i onophore-i nduced rel ease of i nternal stores wi thout
external cal ci um bei ng present (Stei nhardt et al., 1974),
ferti l i zati on apparentl y requi res an i nux of external cal -
ci um to rel l i nternal stores and thereby al l ow prol onged
cal ci um osci l l ati ons to occur (Igusa and Mi yazaki , 1983;
Kl i ne and Kl i ne, 1992b; Mi yazaki , 1995; McGui nness et al.,
1996). Such i nux seems to uti l i ze a capaci tati ve or
store-operated form of cal ci um entry (Parkeh and Penner,
1997) that i n turn depends on the depl eti on of i nternal
cal ci um stores and ei ther posi ti ve or negati ve feedback on
the store-operated pl asmal emmal channel s by such di ffus-
i bl e messengers as cal ci um (Barri tt, 1998), i nosi tol 1,3,4,5-
tetraki sphosphate (IP
4
)(Bi rd and Putney, 1996), and cal ci um
i nux factor (CIF) (Csutora et al., 1999).
On the other hand, i t i s cl ear that oocytes can al so
mobi l i ze i nternal cal ci um stores, and such i nternal rel ease
typi cal l y i nvol ves an IP
3
-medi ated si gnal i ng pathway that
becomes sensi ti zed as the oocyte matures (Chi ba et al.,
1990; Mehl man and Kl i ne, 1994; Abbott et al., 1999). Both
protostome and deuterostome oocytes have the capaci ty for
IP
3
-based cal ci um si gnal i ng, and i n several ani mal groups
IP
3
-medi ated cal ci um rel ease appears to be requi red for
normal ferti l i zati on (Tabl e 2). Conversel y, the abi l i ty to
produce gl obal cal ci um transi ents vi a ei ther RyRs or other
non-IP
3
types of cal ci um rel ease channel s (Wi l l mot et al.,
1997) has been demonstrated for onl y a few taxa (Tabl e 2).
Accordi ngl y, the presence or absence of functi onal RyRs i n
mammal i an oocytes vari es among speci es or even wi thi n
di fferent strai ns, i n the case of mi ce (Jones et al., 1995b).
Regardl ess of whether external or i nternal sources of
cal ci um are uti l i zed duri ng ferti l i zati on, the cal ci um tran-
si ents generated by such mechani sms can faci l i tate vari ous
i mportant processes rangi ng from pol yspermy preventi on to
mei oti c resumpti on. Thi s faci l i tati on presumabl y occurs
vi a di rect or i ndi rect effects of cal ci um transi ents on down-
stream effectors such as cal ci umcal modul i n-dependent
k i nases (CaMKs), cytostati c factor (CSF), maturati on-
promoti ng factor (MPF), mi togen-acti vated protei n ki nase
(MAPK), and protei n ki nase C (PKC) (Gal l i cano et al., 1993;
Whi taker, 1995, 1996; Sagata, 1996; Raz and Shal gi , 1998).
In parti cul ar, the acti vi ty of type II CaMK can be modul ated
by osci l l atory cal ci um transi ents (De Koni nck and Schul -
man, 1998) and i s general l y bel i eved to be essenti al for cel l
cycl e progressi on (Bai ti nger et al., 1990; Lorca et al., 1993;
DuPont, 1998; Johnson et al., 1998).
RECEPTOR-MEDIATED VS SPERM-
FACTOR-BASED SIGNALING PATHWAYS
Essenti al l y two groups of opposi ng, but not necessari l y
mutual l y excl usi ve, hypotheses have been proposed to
account for the upstream pathways by whi ch sperm tri gger
cal ci um transi ents duri ng ferti l i zati on (Dal e and DeFel i ce,
1990) (Fi g. 3). In receptor-medi ated hypotheses (Jaffe, 1990;
Fol tz and Shi l l i ng, 1993), the sperm i s vi ewed as an hon-
orary hormone (Whi taker and Crossl ey, 1990) that gener-
ates the cal ci um ri se from the outsi de-i n by bi ndi ng to
ool emmal surface receptors. Conversel y, sperm-factor hy-
potheses postul ate that fol l owi ng gamete fusi on, the sperm
i ntroduces i nternal l y acti ng mol ecul e(s)i nto the oopl asm to
tri gger the cal ci um response (Swann, 1990, 1993).
Receptor-medi ated hypotheses are consi stent wi th (i ) the
i denti cati on of functi onal sperm l i gands and ool emmal
receptors i n vari ous speci es (Myl es, 1993; Fol tz, 1995;
Ohl endi eck and Lennarz, 1995); (i i ) the demonstrati on that
unferti l i zed oocytes are capabl e of el i ci ti ng cal ci um tran-
si ents vi a si gnal i ng cascades i nvol vi ng i ntegri ns, G-protei ns,
and/or tyrosi ne ki nases, whi ch i n many cel l types are
sti mul ated by receptor acti vati on (Mi yazaki , 1988; Moore
et al., 1993; Shi l l i ng et al., 1994); and (i i i ) the perturbati on
of normal ferti l i zati on-i nduced cal ci um dynami cs fol l ow-
i ng the i nhi bi ti on of G-protei ns or tyrosi ne ki nases that i n
turn may functi on downstream of receptor acti vati on
(Mi yazaki , 1988; Fi ssore and Robl , 1994; Gl ahn et al., 1998).
For more di rect support of a receptor-medi ated pathway,
external appl i cati ons of sperm-deri ved components can
el i ci t a cal ci um transi ent i n oocytes or zygotes of several
speci es (Osawa et al., 1994; Stephano and Goul d, 1997;
Shi l l i ng et al., 1998). However, i n mammal s there i s no
concrete evi dence for si mi l ar external l y acti ng sperm mol -
ecul es that can tri gger cal ci um transi ents vi a receptor-
medi ated pathways (Evans and Kopf, 1998). Moreover, nei -
ther heterotri meri c G-protei ns (Wi l l i ams et al., 1998) nor
tyrosi ne ki nases targeti ng SH2 domai ns on PLC

(Mehl -
mann et al., 1998)appear to be requi red for the ferti l i zati on-
i nduced cal ci um response of mammal s, al though i t i s pos-
si bl e that other receptor-medi ated means of i ncreasi ng PLC
acti vi ty coul d sti l l pl ay a rol e (Mehl mann et al., 1998).
Thus, al though sperm receptors and downstream si gnal i ng
pathways are present pri or to ferti l i zati on, i t remai ns pos-
si bl e that i n some ani mal s sperm-receptor bi ndi ng i s not
speci cal l y requi red for generati ng a normal cal ci um re-
sponse.
Al ternati vel y, sperm-factor hypotheses gai n i ndi rect sup-
port from the l atent peri od that occurs between sperm
ool emmal contact and cal ci um transi ent onset (Whi taker et
al., 1989). In mammal s, for exampl e, sperm fuse wi th the
egg duri ng thi s l atent peri od several mi nutes before the
cal ci um wave starts (Lawrence et al., 1997; Jones et al.,
166 Stephen A. Stricker
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
1998b), whi ch i s consi stent wi th the ti mi ng requi red for the
di ffusi on of a sol ubl e sperm-suppl i ed mol ecul e, al though
not excl usi ve proof for such a mechani sm (Evans and Kopf,
1998). More di rect evi dence comes from the fact that
i ntracel l ul ar i njecti ons of sol ubl e sperm extracts can both
generate a ferti l i zati on-l i ke cal ci um response i n mammal s,
asci di ans, and nemerteans (Stri cker, 1997; Kyozuka et al.,
1998; Swann et al., 1998; Sakurai et al., 1999) and tri gger
acti v ati on that cul mi nates i n pol ar body formati on
(Stri cker, 1997; Wi l di ng et al., 1997)or even cl eavage (Wu et
al., 1997; Fi ssore et al., 1998). Furthermore, the fact that
i ntracytopl asmi c sperm i njecti ons (ICSI) i nto the i nteri or of
oocytes produce cal ci um osci l l ati ons (Nakano et al., 1996)
and heal thy offspri ng (Pal ermo et al., 1996) demonstrates
that i nteracti ons between sperm and ool emmal receptors
are not stri ctl y requi red for normal ferti l i zati on.
Such i nternal l y acti ng acti vators were once bel i eved to be
smal l mol ecul es l i ke cal ci um (Jaffe, 1991) or IP
3
(Tosti et
al., 1993) that were deri ved di rectl y from the sperm and/or
i n the case of cal ci um i ons funnel ed through the sperm
from the extracel l ul ar medi um i n a condui t-l i ke fashi on
(Creton and Jaffe, 1995). Accordi ngl y, cal ci um i njecti ons are
capabl e of causi ng a ferti l i zati on-l i ke cal ci um wave i n sh
oocytes (Yoshi moto et al., 1986). However, nei ther cal ci um
nor IP
3
can ful l y mi mi c the sperm-i nduced cal ci um re-
sponse of mammal s (Swann and Ozi l , 1994), and more
recent data suggest that sperm factors are actual l y protei n-
aceous i n nature (Swann, 1996; Stri cker, 1997; Wu et al.,
1998; Perry et al., 1999).
A 33-kDa osci l l i n protei n was ori gi nal l y proposed as a
possi bl e osci l l ogen i n mammal i an sperm (Parri ngton et al.,
1996). However, subsequent anal yses have rul ed out osci l -
l i n as a cal ci um-mobi l i zi ng agent (Swann et al., 1998;
Wol osker et al., 1998; Wu et al., 1998; Wol ny et al., 1999).
Thus, al ternati ve acti vators such as a truncated form of
c-ki t (Sette et al., 1997), a peri nucl ear consti tuent l i ke
cal i ci n (Ki mura et al., 1998), or PLC (Dupont et al., 1996;
Jones et al., 1998a; Mehl mann et al., 1998) shoul d be con-
si dered, especi al l y i f such sperm-borne oocyte acti vati on
factors (SOAFs)can be shown to generate a ferti l i zati on-l i ke
cal ci um response. In any case, i t remai ns to be determi ned
i f the putati ve sol ubl e acti vator deri ved from sperm (i ) ex-
i sts at hi gh enough concentrati ons to be physi ol ogi cal l y
rel evant (Evans and Kopf, 1998); (i i ) represents a si ngl e
FIG. 3. Di agram of some possi bl e components of ferti l i zati on-i nduced cal ci um si gnal i ng, showi ng receptor-medi ated and sperm-factor-
based pathways as wel l as contri buti ons from i nternal cal ci um rel ease and external cal ci um i nux. Not al l cel l ul ar structures and
mol ecul es i nvol ved i n the ferti l i zati on-i nduced cal ci um response are depi cted, nor does the di agram necessari l y t the data obtai ned from
some speci es (e.g., Urechis). Whether cal ci um i s rel eased from a si ngl e or mul ti pl e stores wi thi n the oocyte/egg has not been establ i shed
for al l ani mal s. Si mi l arl y, i t remai ns to be determi ned i f an i ncrease i n PLC acti vi ty modul ated by tyrosi ne ki nases or other regul ators
necessari l y requi res receptor sti mul ati on or i f i t may al so occur i n response to sol ubl e sperm factors. Moreover, receptor-medi ated and
sperm-factor-based pathways need not represent mutual l y excl usi ve al ternati ves, but i nstead these two si gnal i ng pathways coul d functi on
i n concert duri ng ferti l i zati on. cADPr, cycl i c ADP-ri bose; CaMKII, mul ti functi onal cal ci um/cal modul i n-dependent ki nase, type II; cGMP,
cycl i c guanosi ne monophosphate; CIF, cal ci um i nux factor; ER, endopl asmi c reti cul um; IP
3
, i nosi tol 1,4,5-tri sphosphate; IP
3
Rs, i nosi tol
1,4,5-tri sphosphate cal ci um channel receptors; IP
4
, i nosi tol 1,3,4,5-tetraki sphosphate; NAADP, ni coti ni c aci dadeni ne di nucl eoti de
phosphate; NAADPR, ni coti ni c aci dadeni ne di nucl eoti de phosphate cal ci um channel receptor; PLC, phosphol i pase C; RyRs, ryanodi ne
cal ci um channel receptors.
167 Fertilization-I nduced Ca
2
Signals
Copyri ght 1999 by Academi c Press. Al l ri ghts of reproducti on i n any form reserved.
(Swann et al., 1998) or mul ti pl e mol ecul e(s) wi thi n any one
sperm (Wi l di ng and Dal e, 1998; Perry et al., 1999); (i i i ) i s
wel l conserved across phyl a (Wi l di ng and Dal e, 1997); (i v)
di rectl y affects IP
3
l evel s (Jones et al., 1998a) or al ters IP
3
R
functi oni ng by al ternati ve mechani sms (Gal i one et al.,
1997); and (v) acts i n i sol ati on of (Swann et al., 1998), or i n
conjuncti on wi th, receptor-medi ated pathways (Tesari k,
1998) (Fi g. 3).
FUTURE DIRECTIONS
The current database i ndi cates that both protostomes and
deuterostomes exhi bi t ferti l i zati on-i nduced cal ci um waves,
IP
3
-medi ated cal ci um si gnal i ng, and the abi l i ty to use
i nternal and/or external sources of cal ci um duri ng ferti l i za-
ti on. Such ndi ngs fai l to support a cl ear-cut di sti ncti on i n
cal ci um si gnal i ng modes for these two major groups of
ani mal s and i nstead suggest that fundamental l y si mi l ar
patterns of ferti l i zati on-i nduced cal ci um si gnal i ng exi st
throughout the ani mal ki ngdom, as has been concl uded by
Thomas et al. (1998). However, i n spi te of such general
trends, speci c mechani sms of modul ati ng cal ci um l evel s
duri ng ferti l i zati on may turn out to vary si gni cantl y
wi thi n certai n speci es that ei ther have been exami ned [e.g.,
Urechis (Stephano and Goul d, 1997)] or have yet to be
anal yzed. Thus, for a more compl ete understandi ng of
ferti l i zati on-i nduced cal ci um si gnal i ng, addi ti onal anal yses
are needed, parti cul arl y among nonmammal i an speci es
whi ch can di ffer from mammal s wi th regard to (i ) mei oti c
arrest poi nts reached before ferti l i zati on; (i i ) ori entati on of
the sperm to the ool emma; (i i i ) types of extracel l ul ar
i nvestments around the oocyte; and (i v)i nternal vs external
modes of i nsemi nati on. These suppl emental studi es shoul d
extend beyond ferti l i zati on both to ensure that devel op-
ment proceeds normal l y (Stri cker and Whi taker, 1999) and
to determi ne i f there are ontogeneti c changes i n ei ther the
spati otemporal patterns of the cal ci um response or the
embryos sensi ti vi ti es to vari ous cal ci um-rel easi ng agoni sts
(Sousa et al., 1996a; Stri cker, 1996a). In addi ti on, further
anal yses combi ni ng cal ci um-i magi ng methods wi th el ec-
trophysi ol ogi cal techni ques such as previ ousl y performed
on several ani mal groups (Mi yazaki et al., 1986; McDougal l
et al., 1993; Stephano and Goul d, 1997) shoul d hel p to
el uci date vari ous regul atory mechani sms, parti cul arl y wi th
respect to the modes and rol es of external cal ci um i nux
duri ng ferti l i zati on.
Al though i n some speci es suppl emental si gnal s such as
pH changes may be requi red i n addi ti on to cal ci um tran-
si ents (Goul d and Stephano, 1989), an i ntracel l ul ar cal ci um
ux neverthel ess remai ns an essenti al component of the
ferti l i zati on response i n al l ani mal s exami ned. Combi ned
wi th conti nui ng i nvesti gati ons i nto the upstream modul a-
tors and downstream targets of ferti l i zati on-i nduced cal -
ci um transi ents, further studi es such as outl i ned i n thi s
revi ew shoul d eventual l y provi de an i ntegrated vi ew of how
cal ci um si gnal s al l ow ferti l i zed oocytes and eggs to devel op
normal l y.
ACKNOWLEDGMENTS
Drs. R. Creton, R. Deguchi , R. Fi ssore, M. Goul d, K. Jones, C.
Lambert, L. Li ndsay, A. McDougal l , S. Shen, C. Si merl y, and K.
Swann provi ded extremel y hel pful feedback but are nei ther respon-
si bl e for i naccuraci es nor necessari l y i n agreement wi th the vi ews
that are expressed i n thi s revi ew. Studi es on Micrura alaskensis
were conducted at Fri day Harbor Laboratori es, usi ng l aboratory
space generousl y provi ded by the di rector, Dr. A. O. D. Wi l l ows.
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Recei ved for publ i cati on March 30, 1999
Revi sed May 6, 1999
Accepted May 12, 1999
176 Stephen A. Stricker
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