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1~ ~rIAL OF MI~IAI~ E~06 . . V.E. Pa~oar~u detraction Uses of Mi~nipulation Warred con }fly the promise of biology for i - ~renents in health arm z~pr~ctive performarx~e in humans arm animals, scientists Con diverse fields have recently been aE~1yirg manipulative e~ri~tal Unique to the embryos of a wide range of Species. At both Alar arm cellular levels, material Is being awed, subrace, or all for the a~li~nt of ~ as diverse as stying embryonic inaction and prying genetically superior agricultural animals. He growth of Ear biology has awed a new Tension to the venerable practice of , e _ . a ha e e ha _ a pa ca a ~ a e _ as ~ ~ , ~ embryo manipulation, pairing ~=aalble the induction of Pacific genetic martial or the ~rh~tion of Diogenes gene avidity in Be developing embryo. He pacer of this a~rnadh will be realize anly In `~inatic~n with a consideration of develops1 pro cn He level of organism as a whole. ~ manipulations to be described in this paper are of a cellular rather Han a rnucl~a' or genetic variety. Although He abject of the experiments was not always primarily embryonic ration, together the st ~ ies provide a ~ ium of information on the capacitor of the organism to compensate for cellular perturtations during preimplantation stages of development. m e emphasis will be on the upward regulation of ~~l number, ~ other wards, the ability of an embryo to ccrqxYnsate for a Decrease in cell number at different embryonic stages. Types of Manipulation The indeterminate cleavage of mammals means that A] fates are not precisely foxy face the outset but Ether that calls retain a high degree of devel~tal plasticity or regulative capacity thrift the Fly stages of erdbryogenesis. Leper. evidence sorts the contention that developmental potential of cog Is is gradually nal~ as de~relopnent progresses and oelis beeline established in particular pathways. Den the dentin of differentiation of a ~1 ~ or region of the embryo has }wry i~ev~bly established, its fate is the saIre as its potential arm it can be Ed to be committed or detail. me Canine of this Modular determination remains elusive. ~ 3C] -

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Anion mania n ~ a c~n~taw of Varietal embryology. ~ a~itic~n ~ ~ investigatic~n of Of fate and Via of irxlivi~1 As, He organization of He Kayo as a whole can also be I using m~cnmanipulatic~n Tunis;. He i~actia~s sixteen ~1 1= or grumps of Airs, the influence of parts on He Ale, arm ~ Ale of Optic Bets ~ Ryes can all ~ ~~ Dig cellular ~cmnanipulation. Isolation of parts of an rye to Done there [~ - C: separate f`=u He rest of the Are either ~ ~~, in Chic sit; or in He uterus ~ off -bible procedure. As met. tests the ~nt;~1 of a ~ll or tissue for Irene: develc~t by altering cell arm tissue interactions and, ~ explants, by r~rir~ the Stir influence of the maternal Limit. Alternatively, part of an eribryo can be destroyed or red arm the embryo gram in vitro or ir1 the uterus. He f~ develc~rent of the embryo will provide evidence as to the illportar~ of the misfire part to the develc~nt of He whole arm the capacity of the embryo to USA for Age. cel Is or tissues may also be Bird by transpla~aticxn or Bard between different embryos. In this type of e~peri~nt, genetic Nan; aims for He identification of ache contribution of each Sapient in the Opposite, chivalric embryo. Finally, cells or parts may be added to an ~erw~ complete embryo, arm ~ an extend form of this pmc~~re, whole erbryos can be aggregated together. He sucxxssful covenant of Nitric animus foliate ache aggr~ati~ of two or Ore cx - lete embryos is a tint to the relative capacitor of ~ Orgy mammalian The. Ration in Arabian embryos E - rinds embryologists have made good use of the! irmate Opacity of the n~nalian embryo to adjust its devel~ntal p~rmn to Ate for Actions. Fin the embryo's point of view, this feature ~ pr~nnably advantageous, pr~nricling a measure of flexibility to Add are Sensate for a Terse coalitions that might nicer during gestation. In an animal as complex as the mammal, with a dynamic maternal-embryonic and mat ~ -fetal interaction during gestation, this degree of flexibility provides some insurance for the considerable rep ~ tive investment of each pregnancy. As a practical consideration, parti~,larly ~ the manipulation of human embryos, this regulative able ity allows come leeway in the varicose techniques associated with artificially desisted ccnosption. The fact that the embryo will be able to tolerate I-== than ideal conditions and still develop into a normal individual broadens the range of manipulations that can ethically be applied In mrerc~ainq infertility In humans. In agri~1tura1 animals it will define the limits of ecx~im1ly vi~hie pro. Incus, it is all the refire important to determine the limits of the r ~ ative capacity at all stages of early ~ibr~rogenes~s and to determine differences between different species. In doing so we will be learning about the basic processes of development as well as establishing a firm and reasonable basis for intervention in the reproductive process. 305 -

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Use Shxtvina Radiation I;3b oratory arx] caustic ties Prein~lantati~ Devel~t The Ian embryo Avers ~ ~ alit as it cot ~ ally enters the uterus to he erx] of this pro=, alto he stage at which it d~ so varies and mods (-table 11. Iste ~ cleavage, aids of the embryo Thick up to this tone have been silnilar' logy Cited i;, begin ~ Batten ~ one ark and Space as a peels - e to formation of- the blas~st. With blast~e formation cams the first avert sign of phrenological differentiation of twc ~11 go;, the inner cell man= (ICE) and the alter layer of t_ form as the result of a divergence In gene expression In Me ~ ~l 1 p~latic~ns. Ihis fort differentiation into disti~b ~11 types also heralds the earliest c~nitnent of Ells ~ Pacific cell lies an] results fmn the restriction In potential of the previously tatipotent or at least multipc~t blasts. Folly hatting Frau the zone pellu:ida, We blasters In scan species, such as the horse, Prose arm human, remain spherical, whereas ~ ethers, such as pig err] can, it experts and elevate; considerably before implantation. We tin arm stage at implantation varies ~ different species, as do maternal-fet~ interactions resulting in distinctively different placentstion types. Obese early emerita of prei~r~?lantation ~velc~t have been well studied In the manse from botch Tr~rphologi~a1 arx] ex~ri~n~ Dives arx] a ably full picture has been drawn. Is such information is still Ditty. - ~ ~ ~ - - But for over species of ~r~ologi~]ly, the ~ryc6 of ok Brian Is rile the ~se, ash the tip of events varies (liable 1~. It is 1~oi~ evident foxy ex`~ri~ntal work that ctiff~rxxs in tinier are not ache anly distinctions arm that Eerbr~6 of different species with He sag cell ~ or at the same rrSholoai~1 stare mav be fi0ar~t~llv different in the Dee of ^~ - ~- _ ~ ~ _ determination that has taken place and ache relative potential of blast~e P - Gelatin are cell Potential During Cleavage arm Blas~lation Be Trot Sargent test of ~11 F~rtia1 ~ whether an isolate rbryonic ~11 is totip~ent, that is, why it is Feeble of r~ulatir~ its devel~nt such that it can Agate for an overa:~1 reduction in Chronic ~~l ~ arm produce a viable off~prir~. It Nat be ,, ~ determined if any or all of the calls of an early embryo have this veracity in order to fully define regulation. For example, development of one blasts mere from a 2-cel1 embryo is an indication of individual blastorere totipatency, but both blastc meres must be shown to develop normally before totipotency of 2-cel1 blastomeres in general can be claimed. Likewise, the production of even a single pair of identical twits Rae bisection of an embryo is proof Nat twc halves can be - 3~)6 -

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tatipotent, but the plane of bisection with rent to any airy in the embryo nest be insiders. For the polarized blast~yst, it Is evident Mat ply bisection of the ICM, giving balance half~ryos, can result in manful ~i~ir~ (Garner 1972; 1974) err] so totipot~y of half - Blasts In gereral caveat be claim - . 1) I~o~tory Species: In the mouse, the ~tia1 of single isolate blast to form embryos; apart; to be reprice relatively early (gable 2~. Single blasts fmn the 2~11 stage, but ret later stags, are table of developir~ into Replete, viable off~E?rir~ (lambda & laymen 1983~. Although individual blasts fmn ~,ryo6 up to at let the 8~el1 stage al - ar to be totip~t In terms of the tissues they can produce in a *Libra (Kelly 1975), they are not Table of on anizir~ into viable fetuses in isolation (Pan sent 1976~. In the rat, a complete egg cylinder was reported to have developed from one blastccere of the 2-cel1 stage, although development stopped shortly thereafter ONicholas & Hall 1942~. In more recent experiments, identical twin offspring have been proud frail 2-cel1 blasts meres of the rat Mat et al, 1989~. Single blasts meres frill 4- and even 8-oel1 stages of the rabbit have shown toti~tency (Seidel 1952, 1956; Mbore, Adams & Rowson 1968) indicating a greater regulative capacity of cleaving blasts this specie; than In the ~use. me survival of half mouse embryos can be as high as 65 Extent for the 2~l stage (~ ~ Mt:~ren 1983), arm aver 45 brunt for the 4 - Bell (Rossant 1976), marula (1~a & MbIar~ 1983; Nagashi~na et al. 1984), arm blast~rst (Gardr~ 1974~. Hanover, survival of bath halve of the sex embryo has box d~nstra~ orgy for the 2 cell stage arm the 8- to 16 - x11 stage (MOusatafa & Hahn 1978; Garter & 13raunadk 1981; ]~da & Wren 1983; Naga~hi~a et al. 1984; Table 2~. A recent sty of late rula~e~rly blandest stages of rabbit eF6bryc~s indicate that half embryo survival arc] the survival of botch halves Is Educible in this Species as well (Yang & Foote 1987~. 2) Drastic species: Work in dc~restic Lies has been 1~: schematic but theta has been considerable sum: In the production of i~ti~1 florins of several busies. Ibtip~ of isolated, indivi~ 'amp blast ~ maintained up to the 8~11 stage (1~ & Lore 1974; Willadsen 1981), but no Are than three of We blasts from a 4 ~ 11 embryo and one of the blast ~ f m n an 8 ~ 11 embryo have yet been proved totipo tent. This may be a technical failure but it could also represent a biological restriction in the potential of some of the blastcceres by these stages and indicate that the morphologically similar blastcoeres have already undergone restriction in potential. In another experiment, 4 identical quadruplets were born from a single sheep embryo that had been quartered at the 8-cell stage QWilladsen 1981). If these quarters ccnsisbed of daughter-oell pairs from the 4-oel1 stage, as seem likely fr all the procedure used (Willadsen 1980), then this result ~ ght argue that all 4 blasts meres at the 4-cel1 stage do indeed retain totipotency. A high rate of survival of half embryos to term has been demonstrated for the 2-cel1 stage through the blasts cyst stage in sheep, and both haves of all of the stages have produced ic3~ti=1 twin offspring (Willadsen 1979, 1980; Gatica et al., 1984~. 3D, -

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1` relative potential of single blasts of con euibry=; has not Aim detrain, bet barter embryos fmn the Smell stage have a set of triplets (Willadsen & Polge 1981) arm fmn Me 32 64 - Bell Facula stage, 4 sets of thins (Will~sen et al. 1981), indicating bat at least scene stems of blasts at muse stab are totipotent. Bisection of OC*J embryos has resulted in fur ~ctic~n of identical twins at the early ~ru:la stage to the blasts stage (Oziletal1982; I~thet al. 1983; Oz;1 1983; Willis et al. 1984) arm ~ high ram; of half embryo survival. P - orb louses of ~ryo6 late ~ gestation, hover, clearly indicate that not all embryos that implant am capable of complete develc~rent. A shady of the cam- of fetal mortality in these ~ might well pr~ride insight ins Fusible z~rictions of Gentian or regulative Acid. Little work he been polished on manipulation of ather darestic dies. In the horse, 3 offspring have been sport fmn bid 2-8 cell stages, altha ~ no twin pairs, and 4 offspring comprising 2 sets of twins have been obtained from isolated 4-cel1 blasts meres (Allen 1982; Allen & Pashen 1984). Thus, at least two of the blas*nreres at the 4 ~ 1 stage are totipotent. In the pig, single blastcleres of 2-8-cel1 stages have been isolated and groan ~ vitro to the blasts cyst stage Adore et al. 1969; Bonito & Wright 1983). Recently, several abstracts have appeared indicating that up to 50% of half embryos at the morula to blasts stage can regulate ad develop? into off~prir~ kilt as yet there is ran proof that two halves of the Sam embryo have this capacity (Rorie et al 1985; Naga~hima et al 1987~. In the goat, then is a report that dins can develop halved blast~ysts (Iritani, 1987~. 31 Saunas: Fin this chat sketchy Picture of dares;tic arm - ~ . laboratory specked, it appears that the capacity for independent development of a single blastomere ~ retained to a later stage ~ cleavage in rabbit, sheep and horse embryos than in the meet frequently used model, the mc use. Survival of half embryos may be similar or better in sheer and cows than in mace, and the survival of both halves or even quarters to produce identical offspring has been ~~r-~==fu1 ~ domestic species with significantly fewer attempts, indicating a greater regulative capacity of partial embryos in these species compared with the mouse. The cocurresce of blastulation at a later cleavage division and thus a higher tctal ~11 number in some species, including humans, may allow greater flexibility Embryonic organization. If ~ Is a critics Her of ICM Ads~~ which normal de~rel~nt of Me feds w~11 Scat mar, embryos that blastula~ with a higher Gal ~1 1 nor arm thus a higher proportion of ICM oe11s (Bubhr & Wren 1974) may be able to tolerate a pr~portic~nat=ly greater crease ~ ~11 nuder. Eever, We relatic~ip bean cell red arm embryonic ~rzab;li~ reds to be retain ~ test this idea, arm other factors such as later determination of Specific ~11 lineages may also play an important role In sp~ies Riffles. - 308 -

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The avail able information from the=- and other types of manipulation studies indicate= that mammalian embrycs share with the mn~c~ a considerable flexible ity in regulative development and may also share mechanisms of determination. It is important, however to critically evaluate each species to avoid unwarranted extrapolation between species. Cone red only r~r =~ exceptional animals ~ as the nit armadillo, Sleigh regularly ~~ ~nozyga~s Pleas, to realize what Salem but significant variations ~ Are cloudy related species might well exist. How is Regulation Accomplished? 1) Regulation in the early embryo: From the variation seen in the experiments described above, it appears that regulation does nor always ~~' even ~ situations where the embryo or blast~re has the Bestial to Pram its devel~nt. Ethnical factors affecting regulation, hcrw c~xl~let~ly, hcrw quickly and thresh Hat Urania it is ached are q~estims that nest be appruadhed experinent~lly. Does effective regulation involve only oel1 ~ or Is embryo volume important? Is it recopy that all tissues be recrated to the same Pro? these are questions Hat bear By on Patios Hat are - plier] to Han embryos arx] thus are a matter for urgent consideration. Wd have rectory bed staying these questions using the Use as a ~de] art the folly is a smrr~ry of unpublished work clone in oollabc ration with Dr. K.M. and Dr. J.D. Diggers. We have Emil the recense of ache Use embryo to a 50% reduction by destroying one blast~re at the Shell stage art then following the development of ache resulting half embryos. Tarl~ki (1959a, 1959b) fat that half embryos surviving until =}e 12th day of gestation had r~adhec] the sac stage of clevelc~rent as Errol embryos arx] that ache birch weight of live young derived frae half embryos was not significantly different. Other sties have pelvis eerie Hat Use half embryos adjust to a~r~imat=1y normal size by the 7th day of gestation (I'wis & Rossant 1982~. In contrast, 18 day fetus ~ derived frail half embryos have been shown to weigh significantly lace than those fr=ul centrals (Tsuncda & MeLaren 1983~. Another study found that half embryos produced by destruction of one blasts mere at the 2-cel1 stage regulate the ~ size between 7.5 and 10.5 days of development although the half embryos may became smaller than controls again by 13.5 days (Rends l986~. Our approach has been to examine the immediate results of halving 2-cell embryos on the formation of the blaseocyst and to correlate this with developmental potential. We have exarinel the effects of ct:1ture in vitro verses return of the embryos to the reproductive tract, and also examined a surrc gate in viva environments the immature mouse oviduct' for its ability to support c]mrelc~nt of half embryo;. Enbryo'; were first recovery at the 2 cell stage, 1 blasters was destroyed by lyres, they were Hen either alltu~d ~ vitro or transferred to F~c~r~nant or immature oviducts for 2 days. Ebllc~nng recovery, they were aced for mar p ology, art cell nu ~ an the It art trc = ~ todenn, art sane were retransferred to one day asynchronous foster mothers to determine their further developmental potential. 309 -

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a) homology. In vie o culture results ~ a delay in Antic Revels, but In Cur spry half embryos were at similar ~~Ic~i~1 yes as intact Dots, ir~icatir~ Cat ~rp~s of ye blast~st am 10 dam ~ cast ~ (.~:lnith & local, 1977; Ferlla~ & ~zquie~, 1980~. 1~ was arid of a my hider He of normal develc~rent In vitro than in vitro, although it ~ Legible that a~ at dege~tirg Cargos were Are difficult to recover. b) Sell Nlm~ ark Viability. Within ens Culture critical, C~11 camber ~ half embryo was approximately half that of controls as em fraa our Aries ir~ica~cir~ bat upward ce1 1 Tn~ ruination A; rot burr urIti1 after iT~pla}~tation crams 1986~. Our results indicate that this relationship holds ureter a variety of ^~1~ oonditia~. men me ribryo6 were transferred to fever mothers as ~ mat strict measure of vibbili~r, it was fat bat cell Amber of the prei~plantatic~n ~ryc6 orated with viability and that half embryos Anal all culture conditions had 1cher viability than controls (Figure 1~. this does not present the whole picture, however. Figure 2 provides a diffract representation which su~ivid - ; the reproductive 1~= ink implantation failure as distinct frown failure to Revels after implantation. Among the intact oontro1 embryos, the 106s in viability, which ~ correlated with a lower cell number, can be seen to affect both ~= = ~ _~ ~~ . ~ ~ = _ ~ ~ , _~ ~ =, ~ = _ .~ ~ ~ ~ =1 - mat: i~1~t nor I- 111= I~ 1 =tW~y~, Wl"1 A- W`~ly ~~ cell numbers and viability, however, present a different picture. The proportion of failure due to postimplantatian MOP, i.e. failure to develop normally after evocation of a dcidu~1 response, Increases dramatically, indicating development of the trephecb4derm at the expense _ . . . _ . . . . . . . . . Of the inner cell mass. S. mce blastulation occurs at a particular time regard of the number of cells, and since the proportion of inner cells ~ predicted to be lower in embryos of low ~11 number at the time of blastulation, this result implicate= IoM ratio at that time as being a calve factor in the lowered viability of these embryos. c) ~ ~ Ratio. m e proportion of ICM cells to fetal cells was determined for embryos of each group using a differential Eye method to distinguish between ICM and trophectoderm (Handyside & Hinter 1984~. A preli ~ comparison between half and control embryos for a given culture condition fits with the prediction that embryos with lower call rammer at the time of blastulation will have a lower ICM refill ratio and also with the prediction that a lcm ICE ratio will Case viability. Ibe results are ir~plete as yet he He irr3icatio~ are that In viva creature, even in a nor~pregnant uterus, promotes the formation of a relatively lance Im and that the Semite Is tree of in vice Cute (V.E. E=aioa~u arm K.M. Exert, ur~li~ data). 2) Effect of P~ulati~ on later DE`rel~nt: In a separate stay, half embryos were pried in the sam way kilt were immediately transfer to foster mothers arm allay ~ Replete their develc~nt to - 310 -

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Form. The abject of this study was to assess phenotypic variation among mice produced from half embryos and to compare them with genetically identical mice developing from intact embryos. In other words, half embryos were examined for evidence of a greater phenotypic variation that might indicate incomplete of inconsistent regulation. In ablution to intact control embryos that were recovered brow the mothers and retransferred (transferred controls), an sectional ~ Itch was to compare mice developing from unl isturbed pregnancies (controls). a) Reproductive Success. Preimplantatian, fetal and neonatal losses in the different groups of animals are indicated in Figure 3. The lower Bar - -=S of pregnancy among recipients that received half embryos compared with ~1 embryos argues in favor of a failure that is embryo-related and is consistent with the results of the previous study. Implantation failure and failure during gestation regild not be distinguished in this study since implantation sites were not counted, but during gestation, half embryos were again less s~-ssful than controls, and this indicates a limitation to regulation. An interesting finding was a higher neonatal mortality in mice that developed from half embryos. It is known that neonatal 1~= is Aviated with an increase in the duration of pregnancy and that the duration of pregnancy is increased by small litter size (McLaren 3970~. In our study, embryo transfer, regardless of the embryos transferred, resulted in ~mPd1 litters and the duration of pregnancy was increased in inverse proportion to the litter size. Thus the increased neonatal loss can be explained as an indirect reproductive effect and not as a reflection of a decreased survival potential of mice developing frum half embryos. b) Variation After Birth. A detailed analysis of phencLypic variation among the surviving mice developing from half embryos is underway VIE. Papaioanocu, J. Mkandawire & J. D. Biggers, unpublished data). Preliminary results have shown little variation and no differences that could be attributed to incomplete regulation. m e sex ratio among c^,~=ls, transferred controls and half embryo mice was not significantly different. Maturation events such as age at eye opening and age at vaginal opening were similar for all three groups, as were growth curves for body weight and tail length. Although a number of measures have yet to be analyzed, it Appears that complete regulation has taken place in all aspects of the anion by the time of birth in mice developing from embryos halved at the 2-cel1 stage. The considerable variation seen among developing half embryos Doris preimplantation and pcetimplantation develc~t, Ever, is an irxtication that there are critical points or cream- In ~velc~oent that serve to eliminate embryos that have not regulated. Implantation is certainly one of these critical points since a failure here dcoms the embryo. The narrow wiretap of Cal con patibility by barber arm Euro for successful implantation Is a stringent rent for a particular level of embryonic develc~nt so that development of furx~icn - 311 -

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my have Ken place by this thy even if cell Her ~ not z~a~. Be timing of blast formation Is an indicatic~n Bat this Alar; alff~a~h prei~plantatic~n 1~ associated with half Oryx; in alr Any indicate Bat tsareti~res Be half embryo ~ ~;~l incurable of elici~cir~ a denim ret. If implantation is Awfully initial - , Be ralati~hip between the Her of cells ~ the IN arc In the try: of the beastly may present Adler critical devel~rtal poirrt. Alt~a~h it ~ rut On whether scheme Is a minis Mary Her of IN ~Is, it Is kr~ that these owls stimulate proliferation of the Arm (Gabby et al 1973) Al that the entire as `~l as cone excrae~ryonic Airy are derived fmn the IO1 (Papaioanr~u 1982). A lo IN ~11 ~ at the time of blasts formation caUd create problems at specific stagy (a threshold effect) or put ~rTibryo6 at a ~i~dvan~cage th~a~t develc~ent. Mbre ex~ri~cal work will neto be done to further ill~nirmte the Manic of regulation, not only Be Ablation of cell no, but also regulation In the pr~ortionof clifferentiat~ cell type; arm regulation of furx~tion. Sway of ache forcer acting on embryos to eliminate defective eribry~= or thy that have not successfully regulated will provide insight into Educible i~pr~ver~nts in t~niq~es for hartlling embryos of any species. - 312.

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,}~ENCES Allen, W.R. 1982. Embryo transfer in the horse. In: 'Asian Egg Transfer", C.E. Adams, Ed., CRC Press, Inc., coca Raton, Florida, pp 135-154. Allen, W.R., and R.~. Pashen. 1984. Prc~uction of monozygotic (identical horse twins by embryo m~cromanipulation. J. Reprcd. Fert. 71:607-613. Brackett, B.G. 1978. Experimentation involving primate embryos. In: ' ~ thods in Mammalian Reproduction", J.C. Daniel, Jr., Ed., Academic Press, Inc., New York/ Londonl S.F., pp. 333-357. Buehr, M., and A. Mien. 1974. Size regulation in chimaeric mouse embryos. J. Embryol. exp. Morph. 31:229-234. Davis, J., and H. H-c~eldahI. 1971. ~ ative embryology of mammalian blastocys~ . In: "The Biology of the Blastocyst", R.J. Blandau, Ed., University of Chicago Press, pp. 27-48. Enders, A.C., and S. SchlafRe. 1981. Differentiation of the blastccyst of the Rhesus Monkey. Am. J. Anat. 162:1-21. Fernandez, M.S., and L. Izquierdo. 1980. Blastcac#1 formation in half and double mcuse embryos. Anat. Embryol. 160:77-81. Gardner, R.L. 1972. An investigation of inner cell mass and trophoblast tissues following their isolation Frau the mouse blastocyst. J. Embryol. exp. Morph. 28:279-312. Gardner, R.L. 1974. Microsurgical approaches to the study of early mammalian development. In: "Birth Defects and Fetal Development, Endocrine and Metabolic Favors" K.S. Moghissi, Ed., Thomas, Illinois, pp. 212-233. Gardner, R.L., V.E. Papaioannou, and S.C. Barton. 1973. Origin of the ectoplacenta~ cone and secondary giant calls in mouse blas*ocYsts reconstituted fern isolated trophoblast and inner cell mass. J. Embryol. exp. Morph. 30:561-572. Gartner, K., and E. Baunack. 1981. Is the similarity of monozygotic twins due to genetic factors alone? Nature 292:646-647. Gatica, R., M.P. Boland, T.F. Crosby, and I. Gordon. 1984. Micromanipulation of sheep morulae to produce monozygotic twins. Theriogenology 21:555-560. Hamilton, W.J., and F.T. Day. 1945. Cleavage stages of the ova of the horse, with notes on ovulation. J. Anat. 79:127-130. Handyside, A.H., and S. Hunter. 1984. A rapid procedure for visiting the inner cell mass and trophectoderm nuclei of mouse blas*ocysts in sibs using polynucleotide-specific fluorcchror es. J. Exp. Zoo1. 231:429-434. - 313 -

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IRE 1: Curative call Numbers and Timing (Days Aster Fertilization) of Devel~ne (Modified f~ Pa~ioar~ and At, 1986) faction Cleavage of Aruba_ _Blas~atic~n Entry into 2c 8c UPS ~ C'ell uteri (days] fdays) Days a no no. trays) Days Stage ferenoeC Story Sp~ies louse 1 2 2.5 8-16 3 32 3 Rat 1.5 3.5 4.5 3.s Rabbit 0. 5 1. 5 2 16-32 3 128 3 Tic Species / Pig 0.5-1 2-3 3.5 8-16 3.5-5 16 2.5-3 Shut 1 2 3 4 . 5 64 3 ~ 1 2-4 4-5 ~ 6 5 - 6 3 Horse 1 3 4-5 >15 7-8 5-6 primate . . Rhesus lackey 1 2-3 >4 >26 by 7 4 8a~n 5 5-8 4-5 Hmnan 1.5-2.5 2,5_3b 3-5 16 4.5_5d 64-107 3-4 A: a ES = early sanite; BC = blasts; 16 An b cr~n-runp 1er~. In vitro. 1, Mayer and Fritz (1974); 2, Davis and ~~ldahl (1971); 3, perry and Relays Parts (1982); 5, Willadsen (1980) ;, 6, Hamilton and Day (1945); Steven ark M Heuser and Streetcar (1941); Imps am Harts (1941); Elixirs and S~laf1m (1981) (1978) . - 317 -

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DEBBIE 2: Percentage Noreen Develc~nt of Animated ~ Wry Viable Fetucp" or Off~prir~ Modified thou Papaicx~ & Exert, Sirgle blast fen Half~bFy=; fmn ~ _ Pact 2c 4c 8c 4c 8-16c manila BC Sac 4c 8 Mouse 65 0 0 46 30 42 46 40 0 Rabbit 30 19 11 30 5h~ 52 16 6 100 80 58 31 >ob ~ ~ 16 46 48 Horse - 36 16 ~E: Results fryers different sties are Wined (to text for ref~xs). a Not ~e. b 10 pairs of twins have in produced follawir~ freezing of one half of eat pear c This figure represents only two twin pairs; (W;lladsen, 1980~. - 318 -