The relationship between growth rate and regionalization of amphibian, bird and mammalian embryos is briefly reviewed. In contrast to the others, mammals start gastrulation with few cells but accelerate cell proliferation coincidentally. Experiments are described which demonstrate (1) autonomous development of pieces isolated surgically from such mouse embryos, and (2) an absence of regeneration or regulation. Since such embryos regulate completely after chemically induced random cell death it is postulated that these results reflect developmental determination and a resulting mosaicism that suggests development may have a clonal basis. Maps are drawn, allocating positions to various tissues in the embryo.

Among those classes of vertebrates that are generally oviparous early embryonic development, i.e. cleavage stages, is characterized by very rapid cell proliferation; cell cycle times of 1 h or less are common. No doubt such rapid proliferation of cell is to some extent facilitated by the large store of prefabricated substances e.g. RNA and DNA precursors, proteins and yolk, laid down in the oocyte prior to ovulation and which the developing embryo can readily utilize without recourse to its own genome and biosynthetic pathways. In the wholly viviparous eutherian mammals it would seem that the protected environment of the oviduct and uterus has enabled them to dispense with most of the material normally stored in the oocyte and to be able to rely to a much greater extent upon the functioning of the embryonic genome. Perhaps as a consequence of this, cleavage is characteristically slow with cell cycle times ranging from 10 to over 24 h. Synthesis of new RNA is detectable at the two cell stage.

However even the mammalian embryo, or at least the mouse, is not completely independent of stored maternally derived material essential to its development and lethal maternal effect mutants are known in the mouse (for reviews of these aspects of mammalian development see Rossant & Papaioannou, 1977; van Blerkom & Manes, 1977; Chapman, West & Adler, 1977; McLaren, 1979).

Apart from the obvious, considerable, differences in cleavage rate the progress through the early morphogenetic phases of development also show widely different rates. In amphibian embryos gastrulation is initiated some 12–20 h after fertilization when an embryo may have around 5000 cells (Sze, 1953; Graham & Morgan, 1966; Cooke, 1973, 1979). In birds the embryo is often at the early primitive streak stage at the time of laying (about 18–26 h after fertilization) and may have as many as 80000 cells (Emanuelsson, 1965; Spratt, 1963). In mammals the fastest cleavers would require a week or two to achieve such cell numbers if their early cell division rate was continued, and the slower ones nearly a month. Instead mammals commence gastrulation with comparatively few cells and seem to accelerate their cell division rate coincidentally. According to Snow (1976,1977) the mouse embryo contains only 500–600 cells when the primitive streak forms, but 24 h later has about 12–15 thousand. If this overall proliferation rate is maintained then at the neural plate stage, a convenient end point for the process of gastrulation, the mouse embryo at 8 days will contain between 70 and 100 thousand cells. Other mammalian species including man show similar growth profiles (Snow, 1981). Vertebrate embryos of neural fold stages seem therefore to be of comparable cell number although the course by which they got there may differ. Thus amphibian and bird embryos start by accumulating large numbers of cells then slow down and rearrange the population by various cell and tissue movements into an embryo. Indeed, in Xenopus gastrulation will continue in the absence of cell division (Cooke, 1973) and in chicks is not fundamentally impaired by mitotic inhibitors (Overton, 1958). Mammals on the other hand seem to have acquired the ability to combine rapid proliferation with morphogenesis, and mitotic inhibitors are damaging (see Snow, 1976; Snow & Tam, 1979). It is perhaps understandable that the period of rapid cell proliferation in mammals follows implantation, when the nutritional status of the embryo is considerably improved over its free living cleavage stages.

A combination of accessibility and size has made the amphibian and bird embryos ideal objects for experimental embryology. One of the subjects that has interested biologists concerns cell lineage and the processes involved in the regionalization of embryos into tracts of tissue whose developmental course can be predicted (see Toivonen, 1979). Thus in amphibian (Triturus) embryos Vogt (1925, 1929) was able to mark small groups of cells on the surface of the early gastrula with vital dyes and follow the movement of those cells and thus monitor their subsequent development. His ‘fate maps’ for urodele amphibians have been modified only slightly in the intervening years (Landstrom & Lovtrup, 1979; Lovtrup, 1966); although that for anurans may be significantly different (Keller, 1975, 1976; Youn, Keller & Malacinski, 1980). Experiments in which tissue is transplanted from one part of the embryo to another demonstrate that developmental fate and developmental potency are not necessarily the same. If cells of known fate in the blastula are transplanted to another site in the embryo they are generally able to participate in the normal morphogenesis of their new site (see review by Barth, 1953). However cells of the gastrula may not be so labile in their development (Spemann, 1938) and it is now clear that the process of commitment to a certain developmental course is progressive and may extend over a considerable period of morphogenesis (Forman & Slack, 1980; Slack & Forman, 1980).

In birds a rather similar overall picture is found. Marking of cell tracts with carmine or carbon particles revealed the prospective fates of areas in the chick blastoderm which, at the mid- and late-primitive-streak stages (late gastrula) were confirmed by experiments in which the appropriate embryonic regions were isolated surgically. Such embryonic parts showed considerable autonomic development. At these late stages the fate map thus becomes equivalent to a determination map (see reviews by Rudnick, 1944; Waddington, 1952; Bellairs, 1971; Hara, 1978). Nevertheless the unincubated blastoderm of the chick, duck or quail (pre- or early-primitive-streak stage) can be transected and each piece regulates to form a complete embryo (Lutz, 1949, 1955; Lutz & Lutz-Ostertag, 1963, 1964; Eyal-Giladi & Spratt, 1965; Rogulska, 1968; Eyal-Giladi, Kochav & Menashi, 1976), even though vital dye markings permit the drawing of a fate map for early-primitive-streak stages (see Waddington, 1952).

Such fate maps or determination maps are a prerequisite for further investigation of the cellular events associated with the progressive differentiation of particular organ systems and for studying interactions between tissues associated with normal embryogenesis. In mammalian embryos several studies indicate that complete regulations can occur and normal individuals result from single cells of the embryos at least up to the 8-cell stage (Moore, Adams & Rowson, 1968; Kelly, 1975). Identical twins can be made by separating blastomeres at the 2-cell stage in mice and sheep and quadruplets have been made in sheep from 4-cell embryos (Willadsen, 1979, and personal communication). Single cells or groups of cells from the inner cell mass of day embryos have the potential to contribute to many tissues in the late fetus if grafted into a host blastocyst (Gardner, 1978). However, by this stage of development inner-cell-mass cells have lost the ability to form trophectoderm and are beginning to show signs of further restriction in their developmental potency although there is no evidence that determination of cell lineages in the fetus has yet occurred. From studies on aggregation chimeras it seems unlikely that even a fate map of normal prospective development could be drawn for these early stages of the mammalian embryo. In an aggregate of two 8-cell mouse embryos, the cells of the respective embryos remain as discrete populations and there is very little cell mingling by the time of implantation (Garner & McLaren, 1974). In the chimeric fetuses developed from such aggregates, the cell populations are very thoroughly mixed and there is very little evidence that would indicate regionalisation of the inner cell mass even to the extent that anterior-posterior or dorsoventral axes may be present. Recently, 31 aggregate chimeras, age between and days post coitum (i.e. 3–4 days after implantation and at early-to mid-primitive-streak stages) have been analysed (Matta & Snow, unpublished). These show that the cell mingling is already very extensive, but provide no indication as to how it is brought about. But for Gardner’s data, the simple explanation of the cell mixing in aggregate chimeras would be that cells are determined and a process of sorting out occurs to ensure that cells of like developmental potential become located in the same region of the embryo. Clearly this cannot be so and if cell movement is a normal occurrence in single embryo inner cell masses, then no fate map could be drawn for these early stages. Anatomically the developing epiblast components of the inner cell mass become an epithelium with basement membrane and with an apical bar network at the luminal surface of the cells at about 6 days post-coitum and it seems reasonable to conclude that cell mingling should precede that event, and equally that regionalisation should either accompany that tissue transformation or follow it.

In the mouse a primitive streak forms at about days post-coitum, at which time the anterior posterior axis becomes apparent. The anatomy of subsequent development, the patterns and distribution of mitosis and the short-term vital marking of rabbit embryos (Daniel & Olson, 1966), all suggest that despite the variable geometry of the mammalian embryo, it is probably very similar in layout to the bird embryo and it is tempting to assume that the developmental status and capacity of its parts will be similar (review Snow, 1978).

The development of an in vitro culture system allowing the normal development of early and mid-primitive-streak mouse embryos (Tam & Snow, 1980) has provided an opportunity to carry out some basic embryological experiments on the regionalization of the mouse embryo. Initially attempts were made to graft fairly large pieces of donor embryo into a host of similar stage in order to provide potential duplications of e.g. primitive streak, Hensen’s node, etc. However the presence of a continually expanding yolk sac (exocoelom) invariably forced the grafts apart. Efforts to prevent yolk-sac expansion by inserting as many as three small glass tubes were frustrated by the embryo managing to seal up the tubes with the growing allantois interiorly or by a covering of primary endoderm over the outside projection. The useful observation from these experiments was that a great deal of damage could be done to the yolk sac without apparently disturbing embryonic development at ail, even to the extent that head-fold formation and somitogenesis would occur without the yolk sac at all. Subsequently I have focussed upon the development of isolated pieces and of embryos from which small pieces have been removed.

The culture system used is that described by Tam & Snow (1980). In order to prevent the pieces or the operated embryos sticking to the substrate where the cells then grow as a monolayer destroying morphology, the plastic dishes were coated with 1% agar in Dulbeccos modified Eagles medium. All surgery was done by hand with tungsten needles with the aid of a dissecting microscope. Cultures were usually analyzed after 24 h of development. Because of the limitations of the culture system and the small size of the mouse embryos only early-, mid- and late-primitive-streak stages have been attempted. Figure 1 illustrates the stages of embryos used and marks in the lines along which the majority of cuts are made. The cuts transect all tissues in the embryo, i.e. they pass through the primary endoderm, mesoderm (when present) and epiblast/ ectoderm. Pieces therefore contain all of these tissues. Figure 2 shows exploded diagrams of a late-streak embryo to illustrate the important pieces and their relative sizes. The pieces in the primitive streak have been removed singly or in various combinations, and a few other types of excision have been made. These will be described at the appropriate time.

Fig. 1

Outline drawings of the embryos showing the position of the cuts used in this study. Age of embryo is indicated on left, ps = primitic streak.

Fig. 1

Outline drawings of the embryos showing the position of the cuts used in this study. Age of embryo is indicated on left, ps = primitic streak.

Fig. 2

Exploded diagrams of the embryos showing the position and relative size of the pieces. Pieces 4,5,7, and 8 contain some 150–200 cells.

Fig. 2

Exploded diagrams of the embryos showing the position and relative size of the pieces. Pieces 4,5,7, and 8 contain some 150–200 cells.

Tables 1, 2, and 3 summarize the data. A piece is described as growing simply if it increases in size, and as undergoing morphogenesis if normal embryonic structures can be seen in it with a dissecting microscope. In the latter case growth of the pieces, as measured by protein content, is comparable to that in the intact embryo (Table 4). A brief record of the structures formed by the pieces (Table 2) and by the deficient embryos (Table 3) is given, and some of the pieces and their products are illustrated in Figs 3–7.

Table 1

A summary of the number of pieces and deficient embryos cultured

A summary of the number of pieces and deficient embryos cultured
A summary of the number of pieces and deficient embryos cultured
Table 2

Summary of the development of isolated pieces

Summary of the development of isolated pieces
Summary of the development of isolated pieces
Table 3

Summary of the development of deficient embryos

Summary of the development of deficient embryos
Summary of the development of deficient embryos
Table 4

Protein content of intact embryos and the major pieces before and after our culture

Protein content of intact embryos and the major pieces before and after our culture
Protein content of intact embryos and the major pieces before and after our culture
Fig. 3

(a) A 712-day egg cylinder, the lower half is the embryo, (b) Piece 1 removed, (c) Piece 1 and 3 removed, (d) Piece 5 removed, and (e) Piece 7 removed from a slightly older embryo. Bar = 100μm.

Fig. 3

(a) A 712-day egg cylinder, the lower half is the embryo, (b) Piece 1 removed, (c) Piece 1 and 3 removed, (d) Piece 5 removed, and (e) Piece 7 removed from a slightly older embryo. Bar = 100μm.

Fig. 4

(a) An isolated head fold and heart formed from a Piece 1, (b) A frontal section of such a piece. Bar =100 μm.

Fig. 4

(a) An isolated head fold and heart formed from a Piece 1, (b) A frontal section of such a piece. Bar =100 μm.

Fig. 5

(a) A cultured Piece 2, attached to its yolk sac, (b) A transverse and (c) a longitudinal section of such a piece. Bar × 100μm.

Fig. 5

(a) A cultured Piece 2, attached to its yolk sac, (b) A transverse and (c) a longitudinal section of such a piece. Bar × 100μm.

The development of the major pieces and of the embryos lacking pieces clearly demonstrates a mosaicism of developmental potential in the various regions in the primitive-streak-stage embryo. A comparison of the development of adjacent pieces shows no evidence for duplication of any structure lying at the cut boundary and thus strongly suggests that these pieces have no capacity for regeneration or regulation of either an epimorphic or morphallactic type. In the few cultures carried through 48 h of development these conclusions remain the same. Although development slows down a little during the second day in culture, no additional structures appear in any piece that would suggest regeneration.

From Tables 2 and 3 it can be seen that the capacity to form some structures change with age and also seems to shift from one piece to an adjacent piece. For instance, Piece 1 from a 7-day embryo will not form head structures. This is believed to be because the piece lacks mesoderm at the time of excision and in the culture period has no means of acquiring any; hence proper neural induction cannot occur. However it should be noted that such a piece from a rat embryo will make mesodermal structures in the teratoma it produces when grafted to an ectopic site (Svajger, Levak-Svajger, Kostovic-Knezevic & Bradamante, 1981). Other organ-forming capacities that ‘move’ are for heart and somites. In younger embryos heart-forming capacity does not reside in Piece 1 but is located in Piece 2 and can be severely interfered with by removal of Piece 6 (Table 3). This can be interpreted as showing that heart mesoderm emerges from the anterior end of the primitive streak at about 7 days p.c. and subsequently comes to occupy a more and more anterior position until it is located in the Piece 1 from a day embryo. Whether this shift in position is achieved by active migration of heart mesoderm cells or by differential growth of the embryo which changes shape around them is not known (see Poelman, 1980, for discussion of gastrulation movements in mouse embryos).

Somite-forming ability also changes in time and space (Tables 5 and 6). Piece 1 and 3 alone never make somites but Piece 3 seems to possess somite-generating ability if attached to Piece 2 at 7 days p.c. when Piece 2 alone will not make somites. Piece 2 from an embryo of days or older will make as many somites as an intact embryo (Fig. 6), and removal of Piece 5 from the distal tip of the egg cylinder (a piece which roughly corresponds to Hensens node) reduces somite number by almost 2. The lateral piece referred to in Table 6 (lat) is a piece removed from the right or left side of the egg cylinder at days p.c. or older. It is similar in shape and size to Piece 1 but does not extend significantly into the domain of that piece; it also leaves the central AP axis intact. Removal of the lateral piece interferes with somite formation on the operated side only. In only 4 of the 19 embryos which made somites following removal of the lateral piece were somites made on the operated side. They were the most posterior somites; the somites 1–4 were completely missing in two embryos and very small in the other two but when somites 5, 6, 7 or 8 were formed they were of normal dimension in comparison to the unoperated side. Sagittal halves (sag, Tables 1,2 and 6) made half embryos with normal somite numbers; there is no lateral regulation or regeneration.

Table 5

The somite-forming ability of various pieces and deficient embryos

The somite-forming ability of various pieces and deficient embryos
The somite-forming ability of various pieces and deficient embryos
Table 6

Somite formation in sagittally halved embryos and embryos lacking one lateral side

Somite formation in sagittally halved embryos and embryos lacking one lateral side
Somite formation in sagittally halved embryos and embryos lacking one lateral side
Fig. 6

(a) An embryo from which Piece 4 was removed at 712 days. The prominent mid brain has herniated through the incision and no fore brain has developed. (b) Two embryos from which Piece 7 was removed. Although the tail herniates through the incision the major defect in these embryos is a lack of germ cells. Bar = 100 μm.

Fig. 6

(a) An embryo from which Piece 4 was removed at 712 days. The prominent mid brain has herniated through the incision and no fore brain has developed. (b) Two embryos from which Piece 7 was removed. Although the tail herniates through the incision the major defect in these embryos is a lack of germ cells. Bar = 100 μm.

Three prospective tissues do not move but are of considerable interest in terms of embryonic development. Pieces 6, 7 and 8 contain prospective tail-bud, primordial germ cells (PGCs) and allantois respectively. The location of these regions is the same at 7 and days p.c. indicating an absence of movement of cells through this part of the primitive streak during this period. It is difficult to explain these observations on the basis of epigenetic specification of these developmental potentials since wound healing following removal from a 7-day embryo does not result in replacement of the tissue. This is adequately shown with respect to the allantois but is more easily quantitated by reference to the germ cells. Primordial germ cells in the mouse are alkaline phosphatase (AP) positive and in normal circumstances can only be identified at about days p.c. when they emerge from an AP-positive epiblast at the posterior end of the primitive streak at the base of the allantois ( ,1967; Tam & Snow, 1981). Table 7 gives the number of AP-positive cells (presumed PGC’s) found in isolated pieces or deficient embryos after 24 or 36 h culture. All the PGCs missing from the embryos as a result of removing Pieces 7 and 8 can be accounted for in the isolated pieces. Clearly there is no ability to replace the potential lost by the surgical removal of these parts.

Table 7

Formation ofprimordial germ cells in isolated pieces or deficient embryos

Formation ofprimordial germ cells in isolated pieces or deficient embryos
Formation ofprimordial germ cells in isolated pieces or deficient embryos

The development of the pieces which contain germ cells shows a varied morphology. Piece 7/8 will grow as an allantois and germ cells become distributed throughout the structure (Fig. 7,a) with no apparent tendency to congregate together at any point. However, if Piece 6 is included then in those developing a hind gut invagination (Table 2) all the PGCs are localized around the endoderm lining that invagination (Fig. 7 b). This indicates an affinity between endoderm and PGCs which is reminiscent of the chemotaxis claimed for chick germ cells (Dubois & Croisille, 1970; Rogulska, Ożdżeński & Komar, 1971); but the exact means of route-finding in mammalian germ cells remains mysterious (McLaren, 1981).

Fig. 7

(a) An allantois containing primordial germ cells (PGC’s; darkly stained) developed from Piece 7/8, (b) PGC’s clustered around the hind gut invagination in a cultured Piece 6/7. Bar = 50 μm.

Fig. 7

(a) An allantois containing primordial germ cells (PGC’s; darkly stained) developed from Piece 7/8, (b) PGC’s clustered around the hind gut invagination in a cultured Piece 6/7. Bar = 50 μm.

The presence of these tissues in the primitive steak raises questions about the role of regression movements in somite formation. In chicks a considerable shortening of the primitive streak occurs during early somitogenesis, believed to be brought about by the anterior end of the streak retracing its steps (regressing) and ‘organizing’ the mesoderal tissues into somites as it does so, (see Spratt, 1947 and Bellairs, 1963, 1971, 1979). Measurements of primitive-streak length in the two strains of mice used in my studies show that the maximum length is achieved at days and during the ensuing 24 h (when the embryo will generate 5–7 pairs of somites) shortens only slightly (Table 8). Indeed the shortening would seem to be accounted for entirely by the loss from the posterior half of the streak of the allantois and PGC precursors, and it is to be concluded that regression movements play no part in somitogenesis in the mouse.

Table 8

Changes in primitive-streak length during early somitogenesis

Changes in primitive-streak length during early somitogenesis
Changes in primitive-streak length during early somitogenesis

From the foregoing data it is possible to create a map of areas whose development can be predicted (Fig. 8). In the light of past controversies about fate maps versus determination maps I prefer to regard this as an allocation map, until such time as tissues have been grafted from site to site and the degree of determination of the region has been directly tested. Suffice it to say that the behaviour of the pieces removed from the primitive streak, at several developmental ages and in various combinations shows no evidence for lability in developmental potential and no abnormal arrangements of tissues have been seen. This seems to indicate a rather determined state. However it is in contrast to the picture that emerges from the study of teratomas where the usual layout of pattern is severely disturbed although good organotypic structures can be found. It must remain speculation whether or not Piece 1, for instance, could develop an ability to make additional mesodermal and/or endodermal components since cultures cannot at present be prolonged to times equivalent to those in teratoma studies.

Fig. 8

A map of the embryo allocating positions of the tissues at various ages.

Fig. 8

A map of the embryo allocating positions of the tissues at various ages.

At first sight the autonomous development of embryonic parts seems a contradiction to the recent Mitomycin C experiments of Snow & Tam (1979) in which cell number in the day mouse embryo can be reduced by random killing of cells to about 10% of normal value, without disturbing gastrulation and the resulting formation of a neural-plate-stage embryo with a few pairs of somites (see also Snow, Tam & McLaren, 1981; Tam, 1981, this volume). In those experiments a very rapid reprogramming of development by the surviving cells seems necessary. One mechanism whereby this could be achieved requires that the surviving cells be developmentally labile and that the regionalization of the embryo of reduced size is by a reassignment of ‘positional value’ according to the site a cell now occupies in the embryonic field (Wolpert, 1969,1971).

Alternatively, at the time cells are killed by Mitomycin C the regions of the embryo may already be determined but within each region there are a number of cells that survive the Mitomycin C damage. These cells then proliferate to refill the region or compartment for which they are determined. In the light of the data on isolated pieces a mechanism of the latter kind seems more likely, although it must be borne in mind that the cell killing by Mitomycin C may create circumstances in which lability is induced in the survivors and embryonic regulation with reduced cell numbers is an epigenetic phenomenon.

Should the ‘clonal’ survival of some cells in each determined tissue be correct it is difficult to avoid a comparison with the developmental ‘compartments’ identified in Drosophila imaginai discs (Garcia-Bellido 1975; Simpson, 1981, this volume). Nevertheless there is at present no observation on the excised pieces, or the deficient embryos that would indicate that ‘compartments’, in the sense that they are defined in Drosophila, are also found in mouse embryos.

I gratefully acknowledge the assistance of Patrick Tam for scoring germ cells, and Jacquie Mace for measuring primitive streaks.

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