Heterochrony and the Phylotypic Period

DEVELOPMENTAL BIOLOGY 172, 412–421 (1995)

MINI-REVIEW

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Michael K. Richardson Department of Anatomy, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, England

There has been a resurgence of interest in comparative embryology. It is now important to be able to compare gene expression in different species at similar developmental stages. One phenomenon which may make it difﬁcult to compare embryos in this way is heterochrony—a change in developmental timing during evolution. It is not clear whether heterochrony can affect the intermediate stages of embryonic development, when many important genes involved in pattern formation are expressed. A prevalent view is that these so-called phylotypic stages are resistant to evolutionary change because they are when the body plan is laid down. Haeckel’s famous drawings, which show different vertebrates developing from virtually identical somite-stage embryos, are still used to support this idea. I have reexamined the morphological data relating to developmental timing in somite-stage embryos. The data reveal striking patterns of heterochrony during vertebrate evolution. These shifts in developmental timing have strongly affected the phylotypic stage, which is therefore poorly conserved and is more appropriately described as the phylotypic period. This is contrary to the impression created by Haeckel’s drawings, which I show to be inaccurate and misleading. The study of gene expression in embryos which show heterochrony could give important insights into evolutionary and developmental mechanisms. ᭧ 1995 Academic Press, Inc.

INTRODUCTION expression which characterises animals. It is claimed to be expressed at the stage of development when the body plan Comparative and evolutionary biology are becoming in- or Bauplan becomes visible. This stage is known as the creasingly important in developmental studies. One reason phylotypic stage (reviewed by Raff, 1994). for this is a renewed interest in the relation between evolu- While there are many excellent reviews and discussions tion and development (Gould, 1977, 1992; Bonner, 1982; of heterochrony, little has been written about develop- Goodwin et al., 1983; Raff and Kaufman, 1983; Gans, 1988; mental timing in the phylotypic stage. Thus there is dis- Wolpert, 1990; Hall, 1992; Hanken and Thorogood, 1993; agreement about when the phylotypic stage appears, Akam et al., 1994). In particular, changes in developmental whether it is a useful concept at all, and whether phylotypic timing (heterochrony) are considered to be important in pro- characters in vertebrate embryos (pharyngeal pouches, so- ducing morphological change during evolution (De Beer, mites, neural tube, and a chambered heart, for example) 1951; Gould, 1977, 1992; McKinney and McNamara, 1991). develop at comparable times in different species. In fact, Another reason is that genes involved in pattern formation the whole question of timing and stages in development is have been identiﬁed, and these genes often show strikingly a neglected one, and the last detailed survey was by Witschi similar patterns of expression in different species (see, for (1956). I have therefore reviewed the comparative morpho- example, Fietz et al., 1994). This makes comparative mor- logical data on vertebrate development at stages when the phology important, because one wants to correlate gene ex- main organ primordia appear (the extraembryonic mem- pression with morphology. branes are beyond the scope of this article and are not in- Developmental biologists are working towards the inte- cluded). gration of classical, evolutionary, and comparative embryology with the data from molecular studies (Tabin, 1992; SOURCES OF DATA ON Tabin and Laufer, 1993; Dolle et al., 1993; Kenyon, 1994; DEVELOPMENTAL TIMING Duboule, 1994). One idea to come from this work is the zootype concept (Slack et al., 1993). The zootype is the What we know about developmental stages in vertebrates name given to a conserved pattern of developmental gene comes from a very small number of species. However, these

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/ m4450f8041 11-07-95 07:48:30 dbal Dev Bio Heterochrony in Development 413 provide sufficient data for a reasonably wide comparative tube develops in early somite stages, and the liver diverticu- survey to be made. The data can be found in two types of lum and limbs appear in midsomite stages. In Xenopus yet sources: another pattern is seen. The liver diverticulum appears very early and slowly deepens; the heart tube develops in mid- (i) Normal tables. These consist of detailed information somite stages and the limbs in postsomite stages. Other on the internal and external morphology of embryos. Nor- heterochronic effects are seen. Retinal pigmentation is mal tables constitute a valuable but neglected data source markedly precocious in Xenopus. In the lizard and the an- for evolutionary studies. The most important are Keibel amnia,1 the heart tubes appear later than in mammals, and (1897–1938) for a variety of species and Nieuwkoop and the lens and nasal placodes appear earlier. Figure 1 also Faber (1967) for Xenopus laevis. shows that organogenesis lags behind somite segregation in (ii) Series of normal stages. Intended for the rapid staging the dogfish and the lungfish compared with other species. of embryos in the laboratory or the field, these consist of data on the external morphology of embryos. The lack of description of internal anatomy and the grouping of a range OTHER EXAMPLES OF HETEROCHRONY of different ages into a single stage reduce the value of these studies for comparative purposes. Many series leave out The Neural Crest such essential information as somite number (Lynn, 1942; McCrady, 1938). References to published normal stages can The time of onset of neural crest migration varies in rela- be found in Bellairs (1971); Gribnau and Geijsberts (1981); tion to neural tube closure in different species (Hall, 1988). Fox (1984); and Gans et al. (1985). Furthermore, we have pointed out that in many vertebrates with larval stages, the neural crest pigment cells in the skin differentiate at a much earlier stage of development than DEVELOPMENTAL SEQUENCES AND that in higher vertebrates (Richardson et al., 1989). For ex- HETEROCHRONY ample, in lampreys and fish, body melanocytes typically appear in late somite stages, near the time that retinal pigmentation begins (Damas, 1944; Piavis, 1971; Hisaoka and Heterochrony is common in the development of inverte- Battle, 1958). In higher vertebrates, skin pigment appears brates (reviewed by Gould, 1977; Raff and Wray, 1989; Mc- much later (Richardson et al., 1989). Kinney and McNamara, 1991; Raff, 1992). Much of the literature on heterochrony during vertebrate evolution refers to late stages—after hatching or birth (reviewed by Gould, Lampreys 1977). The retention of larval features by sexually mature Lampreys form many somites (Damas, 1944; Piavis, axolotls is a familiar example of this. More important for 1971). The embryos start moving when they only have 20 the purposes of this review are examples of heterochrony somites and hatch shortly afterwards. Remarkably, the op- in embryonic stages, when many genes involved in pattern tic evaginations appear at the 26-somite stage, later than in formation are expressed (Slack et al., 1993). Relatively little most other vertebrates. As in Xenopus, the liver diverticu- has been written about heterochrony at these stages, and a lum begins early (at 10 somites) and slowly deepens. The comparative study of the data is often necessary to find heart appears relatively late in lampreys, as it does in the heterochronic effects. other anamnia. One way to analyse developmental data for evidence of heterochrony is to examine developmental sequences in different species (for a discussion of developmental sequences Limb Development in Amphibians see Alberch, 1985; Raff and Wray, 1989; Langille and Hall, There is considerable variation among amphibians with 1989). The primary data which I have used to prepare devel- respect to the sequence of appearance of the limbs. In Xeno- opmental sequences come from Normal Tables and are pre- pus the hindlimbs appear first (Nieuwkoop and Faber, 1967), sented graphically in Fig. 1. The metric is somite count, and in Ambystoma, the forelimbs appear first (Harrison, which is simply one arbitrary way of expressing the develop- 1969; Schreckenberg and Jacobson, 1975). Even within a mental age of an embryo. As can be seen, the timing of single genus of amphibians, there are significant differences some features is relatively constant among vertebrates. in developmental timing; the limbs buds are retarded in the Usually, the optic evaginations and otic placodes appear in axolotl Ambystoma mexicanum compared to those in A. the earlier somite stages; the gall bladder diverticulum and maculatum (Schreckenberg and Jacobson, 1975). In Rana Mullerian duct anlagen are constant markers of the late also, the hindlimb buds appear at different stages in differ- somite or postsomite period; and the thyroid diverticulum ent species (Shumway, 1940). and four pharyngeal pouches appear between these times. In some invertebrates, direct development (the omission However, other features are highly variable in their time of appearance (Fig. 1). The endocardial tubes, liver diverticulum, and fin buds of the lungfish appear in relatively ad- 1 Anamnia (or anamniota): animals which do not develop an am- vanced stages of somite segregation. This is in strong con- nion (fish and amphibians). Compare with amniota, animals which trast to the three mammals analysed; in these the heart develop an amnion (reptiles, birds and mammals).

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FIG. 1. Developmental sequences in different species plotted against somite count and standardised for comparison with the human sequence. Numbers indicate the total somite count for that species given in the reference. To simplify the analysis, it was restricted to a few representative species and characters, for which good data were available. The sequences, which are not causal ones, have been

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FIG. 2. One of Haeckel’s (1891) plates depicting a conserved stage in vertebrate development (only the mammals are shown here, but he published similar plates for other classes of vertebrate). Top row from left to right: opossum (30 somites), pig (31 somites), deer (39 somites), cow (31 somites), dog (39 somites), bat (42 somites), rabbit (42 somites), human (35 somites). Somites were counted from the plates. Compare with the embryos depicted in Fig. 3.

of larval stages) is associated with heterochrony (Raff, 1992). just before gastrulation in Chamaeleo, at the start of gastru- The same is true in amphibians. The frog Eleutherodactylus lation in Vipera, in the late gastrula in Lacerta, and after has no tadpole stage (Lynn, 1942; Elinson, 1990). The early gastrulation in some turtles (Hubert, 1985). Moffat (1985) embryonic stages in this species, including neurulation, compared the development of the tuatara (Sphenodon) with show no unusual features, and the adult is essentially a that of the lizard (Lacerta). She noted that the somites ap- normal frog. But the somite stages are different from those pear only after the neural tube has closed almost fully in in other anurans. The limb buds are formed very early— Sphenodon, and this is surprisingly late. The onset of tor- shortly after neurulation. In Xenopus and Ambystoma the sion is also late. Ewert (1985) noted differences in the time limb buds appear much later (Nieuwkoop and Faber, 1967; of development of the paraphysis and cerebellum among Harrison, 1969; Schreckenberg and Jacobson, 1975). turtles.

Reptiles Birds Several heterochronic shifts have been described in rep- There appears to be little diversity in embryonic develop- tile development. Primordial germ cells can ﬁrst be detected ment among birds, and they have been described as having

drawn up with reference to somite number because the somite period corresponds approximately to the putative phylotypic stage. Furthermore, somites are segregated sequentially and provide a good measure of the progress of development at these stages. The fact that total somite counts vary between species does not invalidate the comparison because it is only the sequence which is being compared. Standardising the data as a percentage of total somite number does not alter the developmental sequences and hides any heterochronic shifts in the timing of somite segregation itself. The data point for ‘‘4th pharyngeal pouch’’ is not available for Necturus.

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footplate and closure of the posterior neuropore are all later in mice, whereas the liver rudiment, lens, and olfactory placodes appear earlier. The development of the apical ridge of the mouse limb is delayed compared to that in other tetrapods (reviewed by Wanek et al., 1989).

MECHANISMS OF HETEROCHRONY

Many mechanisms for producing heterochrony have been proposed and are reviewed elsewhere (Raff and Wray, 1989; McKinney and McNamara, 1991). Work on invertebrates has identified genes which may be involved in the control of developmental timing. The lin-14 gene of Caenorhabditis elegans is a good example (Ruvkun and Giusto, 1989). Little is known about the control of developmental timing in vertebrates, although several cell-autonomous mechanisms FIG. 3. Embryos from standard normal tables at equivalent somite have been proposed (Cooke and Smith, 1990; Holliday, stages to Haeckel’s stage 1 (top row in Fig. 2). (a) Rabbit (Minot 1991). The progress zone model, in which cells in the limb and Taylor, 1906, Fig. 27). (b) Human (Keibel and Elze, 1908, Fig. 8). measure time by counting cell divisions, is well known Haeckel’s drawings (Fig. 2) do not give an accurate representation of (Summerbell et al., 1973). Temporal colinearity in the ex- these species and this view is supported by comparing his drawings pression of Hox genes could provide a mechanism for mark- with other standard references such as O’Rahilly and Mu¨ ller (1987) for the human embryo; McCrady (1938) for the opossum, and Sa- ing time, particularly with respect to limb development and kurai (1906) for the deer. maturation along the primary axis (Duboule, 1994). In the mouse, disruption of the Hoxd-13 gene has effects on limb development which have been interpreted as heterochronic (Dolle et al., 1993). the unity of a single reptilian order in this respect (Billett Differences in the rate of development along the primary et al., 1985). However, it should be remembered that very body axis could account for some examples of heterochrony. few species have been studied in detail. For example, one McCrady (1938) found that the forelimb and other anterior would like to know the details of development in atypical structures were precociously developed in the opossum em- species such as the hoatzin (Opisthocomus hoazin), whose bryo. This could be related to a delay in the progress of young climb by means of claws on their wings. maturation along the anteroposterior axis, although more data are needed to answer this question conclusively. It could be that the opossum is not a case of forelimb accelera- The Opossum and Other Mammals tion, but of delay in the development of posterior structures. The opossum has been described by McCrady (1938) as It would be useful to look at the timing of expression of showing numerous differences in developmental timing Hox genes along the primary axis in this species. Axial ef- compared with that in other vertebrates. The pharyngeal fects could explain why, in general, the forelimb develops pouches, pancreas, somites, lung buds, otic placodes, myel- earlier than the hindlimb in most animals (Fig. 4). However, encephalon, and forelimb bud are all accelerated compared it has to be remembered that in Xenopus, the house shrew, to those in other mammals. The precocious forelimb devel- and the alligator, the hindlimb buds appear first (Nieuw- opment is particularly striking; the earliest sign is a mesen- koop and Faber, 1967; Yasui, 1993; Ferguson, 1985). chymal condensation at approximately the 9-somite stage. Other possible axial effects include the dissociation be- McCrady also noted that the vascular system develops ear- tween organogenesis and somitogenesis. In Squalus and lier in mammals than in the lizard and ascribed this to Neoceratodus, most organ primordia make their appearance homoiothermy. He interpreted some of the heterochronies when many somites have already been segregated (Fig. 1). in the opossum as adaptations to special features of marsu- In the case of Squalus this may be related to the fact that pial reproductive biology. Thus he says that the precocious a large final number of somites is formed; one could argue forelimbs are needed by the newborn to climb into the that the somites have to be laid down faster in this case. mother’s pouch. The glass snake also forms a large number of somites and Gribnau and Geijsberts (1981) made a detailed compari- the hindlimb buds in this species appear at the 65-somite son of developmental timing in rodents and primates. Apart stage (Fig. 4). In most vertebrates limb buds appear when from minor differences, such as the time of closure of far fewer somites than this have formed. Somite formation Rathke’s pouch, they found little evidence of heterochrony. also shows dissociation from the timing of neural tube clo- Comparisons between mice and humans show a similar sure. Thus about 13 somites have formed before the neural picture, with only minor differences in timing (Theiler, folds have started to fuse in the opossum (McCrady, 1938); 1989). Thus the appearance of the cloacal membrane and 7 have formed in the mouse (Theiler, 1989), and in Sphen-

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FIG. 4. Dissociation between somite number and the timing of limb bud development in different vertebrates. Somite number is given for the time when the limb or ﬁn primordia ﬁrst appear as distinct buds. Limb buds can develop at any time during the somite period and later, depending on the species. There are no obvious taxonomic trends in this dissociability.

odon, somite segregation does not even begin until the neu- which vary between species (Freeman, 1982; Wolpert, 1990). ral tube is almost completely closed (Moffat, 1985). Waddington (1956) is typical of these views:

It is at an intermediate period, early but not right at the beginning, THE PHYLOTYPIC PERIOD that embryos are most alike; probably because this is the time at which the basic structure of the animal is being rapidly laid down, and it is very difﬁcult for evolution to alter anything at such a One needs to know how the heterochronic effects de- crucial period without throwing everything into confusion (Wad- scribed above relate to the phylotypic stage, when im- dington, 1956, p. 9). portant genes are expressed. The conserved, phylotypic stage is said to contrast with both earlier and later stages, Phylotypic or conserved stages have been deﬁned for a

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FIG. 5. Developmental sequences in two very different vertebrates: The lamprey and human. This ﬁgure emphasises the signiﬁcant effects that heterochrony has had on embryonic stages of vertebrate development. Notice, for example, the retardation of the lens and nasal placodes in the human.

number of invertebrate groups (reviewed by Brusca and ceral clefts indicates that his drawings are a mixture of Brusca, 1990; Slack et al., 1993; Nagy and Carroll, 1994; criteria from different stages. Raff, 1994). The idea of a conserved stage in vertebrate de- The ‘‘pig’’ embryo, for example, would be undergoing tor- velopment has a much longer history. sion at the somite stage depicted (Keibel, 1897) and many of the embryos should have distinct forelimb buds. This can be seen by comparing Haeckel’s drawings with published Haeckel’s Drawings embryos of the same somite stage (Fig. 3). His ‘‘opossum’’ is inaccurate because the forelimb is precocious in this spe- Haeckel (1891) published a series of comparative draw- cies and would be prominent at this time (McCrady, 1938). ings showing different animals arising from virtually identi- The hyomandibular (auditory) groove and neighbouring cal somite-stage embryos. It is surprising to find that these structures do not resemble the mammalian condition (cf. famous old drawings are still the main evidence for a con- Fig. 3). In the rabbit and human embryos, the branchial served stage in vertebrate development. The plates (Fig. 2) apparatus is depicted as fish-like, and this may be a reflec- are very influential and are still reproduced in textbooks tion of Haeckel’s ideas on recapitulation. Earlier editions of (Alberts et al., 1994). Haeckel’s figures were published in this work (e.g., 1874) had even more implausible figures in his Anthropogenie (1891). As Gould (1977) has pointed out, which fish embryos were drawn to look almost the same this was essentially a popular work and so it is somewhat as human ones. These famous images are inaccurate and puzzling that the figures have been accepted uncritically. give a misleading view of embryonic development. Haeckel’s ‘‘stage 1’’ is described as having visceral clefts but no limb anlagen (the plate for mammals is reproduced here in Fig. 2, top row). However, his stage 1 embryos are Modern Concepts of a Conserved Stage not consistent with other data on the development of these There is some disagreement about what form a phylotypic species. The condition of the limb fields, somites, and vis- stage might take in vertebrates and a variety of definitions

/ m4450f8041 11-07-95 07:48:30 dbal Dev Bio Heterochrony in Development 419 has been given. Analysis of the comparative data indicates CONCLUSIONS AND PROSPECTS that while these definitions do refer to a time when some phylotypic characters are appearing, they are not conserved Much of the controversy relating to developmental tim- stages. Recent definitions of a conserved stage include the ing has arisen from confusing the putative phylotypic stage following: with Haeckel’s idea of a conserved stage. There is certainly a (i) The ‘‘pharyngula’’ stage (Ballard, 1981). This is time in development when the main organ primordia appear when a paired series of pharyngeal arches and pouches is and there appears to be striking conservation in the patterns present. The total number of pharyngeal pouches varies be- of gene expression at this time. However, this stage shows tween species, but if embryos with four pouches are com- rather poor conservation of morphology because structures pared, it is seen that the degree of development of organ appear at different times in different species (Fig. 5). Phylo- primordia differs between species. In the lungfish, for exam- typic characters appear throughout the whole course of the ple, the heart tubes have appeared by this stage but the fin somite period and some, such as the heart chambers, are buds have not (Semon, 1901); in Xenopus, neither heart nor differentiated later than this. It is therefore more appro- limb primordia have appeared (Nieuwkoop and Faber, 1967); priate to speak of a phylotypic ‘‘period’’ because this avoids and in the lizard Lacerta, both are present (Peter, 1904). the idea of a narrow timepoint implied by the word ‘‘stage.’’ (ii) Early somite embryos (Wolpert, 1991). At early Duboule (1994) uses the term ‘‘phylotypic progression’’ for stages of somite segregation, embryos vary greatly in terms similar reasons. of which organ primordia are present. For example, the lung- The study of developmental genes in embryos which fish Neoceratodus has no heart tube, fin, liver, thyroid, or show heterochrony could provide important information gall bladder anlagen at early somite stages (Semon, 1901; about evolution and development. It is hoped that the mor- Kemp, 1982), while humans have a heart primordium but phological data reviewed here will be useful in identifying no limb buds (O’Rahilly and Mu¨ ller, 1987). interesting examples of heterochrony. We need to be able (iii) The tailbud stage (Slack et al., 1993). This stage, to compare temporal and spatial patterns of gene expression too, is poorly conserved. The tailbud first appears at the in different species. However, it is not always easy to make 10-somite stage in the urodele Necturus (Eycleshymer and a comparative analysis of published molecular data because Wilson, 1910), at 13 somites in human (Keibel and Elze, of the tendency in the literature to describe embryos as 1908), at 22 in the chicken (Keibel and Abraham, 1900), at ‘‘Embryonic Day x,’’ rather than giving a more accurate the 32- and 33-somite stages in the lungfish and dogfish, indication of morphological stage. respectively (Semon, 1901; Scammon, 1911), at 40 somites Data on developmental timing could prove useful in tax- in the lamprey (Damas, 1944), and at 65 in gymnophiona onomy, although many more species need to be studied (Sammouri et al., 1990). Different combinations of organ before we can have a complete picture of heterochrony in primordia are present at these stages (Fig. 1). In summary, the vertebrates. Akam et al. (1994) have pointed out that heterochrony in vertebrate evolution makes it impossible the decline of comparative anatomy was partly because it to define a common stage at which the embryos of all verte- had been pushed to its limits. This is certainly not the case brates have the main organs present as undifferentiated pri- with comparative embryology, which went out of fashion mordia. too early. Only a few types of vertebrate embryo have ever been studied in any detail, and the increasing difficulty in collecting specimens from the wild may mean that much of the uncharted territory in comparative vertebrate embry- DISSOCIABILITY ology will never be explored.

Heterochrony implies that the timing of different events ACKNOWLEDGMENTS can be varied independently. This property is called dissociability (Needham, 1942) and is shown here to be particu- I thank Dr. C. Chumbley for supporting this work and reading larly associated with the development of the nasal and lens the manuscript and Professor L. Wolpert, Dr. N. Brown, and Dr. P. placodes, somites, heart tubes, and limb buds. The time of Francis-West for their valuable comments. appearance of the limb buds is exceptionally variable (Fig. 4). They appear at early somite stages in some frogs (Lynn, 1942); at midsomite stages in many higher vertebrates; and REFERENCES at postsomite stages in Xenopus (Nieuwkoop and Faber, 1967). It is not known whether this variation is due to differ- Akam, M., Holland, P., Ingham, P., and Wray, G. (1994). (Eds.) The ences in the time at which the limb ﬁelds are speciﬁed or evolution of developmental mechanisms. Development (Suppl.), differences in the timing of their subsequent development. 241. It would therefore be of great interest to compare the time Alberch, P. (1985). Problems with the interpretation of develop- of expression of Hox and other genes involved in limb devel- mental sequences. Syst. Zool. 34, 46–58. opment in these species. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson,

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