Inductive interactions in early amphibian development

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<ul><li><p>Inductive interactions in early amphibian development </p><p>H.V. New and J.C. Smith </p><p>National Institute for Medical Research, London, UK </p><p>Current Opinion in Cell Biology 1990, 2969-974 </p><p>Introduction </p><p>In this review, we examine progress made since the pre- vious review in this journal [l] in our understanding of the sequence of inductive interactions responsible for es- tablishing the body plan of the early amphibian embryo. Most studies on inductive Interactions in amphibia have concentrated on the South African clawed frog Xenopus kmvis and so we have restricted almost all discussion to these. We also consider how recent results may shed light on inductive interactions in amniotes, which, until recently, have proved difficult to analyse. </p><p>The first Inductive interactions during early development result in the generation of the mesoderm followed by the neurectoderm. In each case, induction involves the for- mation of characteristic tissue types as well as their re- gionalization, although these processes are often consid- ered separately. For mesodenn formation, it is still con- venient to discuss much of the work in the framework of the three-signal model (see [l], and Fig 2 therein). Brie&amp; it appears that at the early blastula stage the Xeno pus embryo consists of only two cell types: presumptive ectodenn in the so-called animal hemisphere and pre- sumptive endoderm in the vegetal hemisphere. In addi- tion, there is, in the vegetal hemisphere, a dorsoventral polarity that is dehned 45-90 min after fertilization by the direction of rotation of the cortex of the egg relative to its cytoplasmic core. This polarity results in the side of the embryo on which the sperm entered becoming ven- tral and the opposite side becoming dorsal (raiewed in Ml. </p><p>During blastula stages, signals from the vegetal hemi- sphere of the embryo act on overlying equatorial cells to induce them to become mesoderm. There seem to be at least two types of mesoderm-inducing signal. One, em- anating from the dorsal vegetal quadrant (opposite the sperm-entry point), induces dorsal mesoderm such as muscle and notochord. The other, derived from a larger ventral vegetal sector, induces predominantly ventral tis- sue types such as blood and mesothelium. </p><p>The large region of ventml mesoderm resulting from the latter signal becomes subdivided by the third signal of the three-signal model. This is produced by the newly in- duced dorsal mesoderm: Spemanns famous organizer. This third interaction has been called dorsalization, and </p><p>results, for example, in some of the ventral mesoderm becoming specified to form kidney while other regions become muscle. Dorsalization begins at the early gastrula stage, when the mesoderm is also believed to start acquir- ing anteroposterior patterning. </p><p>Neural induction, the second major inductive interac- tion, also takes place at gastrula stages. It occurs through the iniluence of dorsal mesoderm on dorsal ectoderm, and involves the respecification of ectoderm to become neurectoderm, together with the imposition of antero- posterior pattern. The traditional view of neural induction has been that the mesodermal signal acts mdially dur- ing gastrulation, the involuting dorsal mesodermal cells acting on the overlying layer of ectodermal cells iirst to induce anterior neurectoderm and then to posteriorize it (reviewed by Nieuwkoop et al In i%e Epigenetic Nu- ture of Early chordate Devekpzent. Cambridge Univer- sity Press, 1985, pp 150-179). Recent results, however, in- dicate that neural induction may start even before the on- set of gastrulation and that it can occur tangentially within a tissue layer [3] (see [l] for review; but also, see [4]). </p><p>The question of regional specification is central to an understanding of inductive interactions in early devel- opment. The above summary of the inductive events in early amphibian development referred, for example, to the specification of dorsal and ventral mesoderm through the action of distinct mesoderm-inducing signals. This ls a convenient description of the differentiated cell types that are induced by each signal, but a major difllculty is that these cell types are usually assessed many hours, if not some days, after the initial interaction. In the case of mesoderm induction, this is also after major cell move- ments have taken place. There is thus the opportunity for additional inductive interactions to occur between in- duced cells so that the linal outcome may reveal little about the result of the initial interaction. Furthermore, although difTerentiated cell types such as muscle and no- tochord provide useful indications of initial dorsoventral position, they do not define anteroposterior position. It is important, therefore, to discover early markers of po- sition in the embryo, particularly markeis of anteropos- terior position, and to establish how their expression is controlled. </p><p>Much work this year has concentrated on these ques- tions, making use of known and newly discovered </p><p>Abbreviations bFGF--basic FCF; FGHbroblast growth factor; F!W-follicle-stimulating hormone; MMesoderm-inducing factor; </p><p>TCMransforming growth factor. </p><p>@ Current Biology Ud ISSN 0955674 %! </p></li><li><p>970 Cell differentiation </p><p>mesoderm-inducing factors as well as the posterioriz- ing effect of retinoic acid previously discussed [l]. Few markers of anteroposterior position in the mesoderm have been described and so our discussion of this axis is largely restricted to the neurectoderm. </p><p>Mesoderm induction </p><p>Mesoderm-inducing factors A major iinding in the last year has been that activin is a potent mesoderm-inducing factor and that many of the inducing factors previously studied are either ac- tivin itself or activin homologues [5-91. These include XTC-mesoderm-inducing factor (MIF) XTCMIF, made by the XenopusXK cell line (Smith, Development 1987, 99:314), and WEHIMIF, secreted by WEHI- monomye- kxytic leukemia cells (Godsave et al, Development 1988, 1023555566). PIF, a mesoderm-inducing factor made by the macrophage cell line P388Dl [lo] has also been shown to be an activin [9]. </p><p>Activins are members of the transforming growth factor (TGF)j3 superfamily, originally identified by their effects on the release of follicle-stimulating hormone (FSH) and on erythroid differentiation (for review, see Ling et al, Vit Harm 1988, %:I-46). They consist of dimers of the in- hibii p chain, either pApA (activin A), pApB (activin AB), or j&amp;h (activin B). Although all three combinations of f3 chain are active [ 111, activin B has not yet been iso- lated from natural sources. The actions of activin in FSH release and erythroid differentiation assays are antago- nixed by the inhibins, heterodimers consisting of one of the above- mentioned j3 chains and a larger a chain. However, inhibin does not inhibit the action of activin in mesoderm induction [ 51. </p><p>It is not yet clear whether activin is present in the early Xen@us embryo. Preliminary studies mentioned by van den Eijnden-Van Raaij et al [7] suggest that the Xenopus blastula contains FSH-releasing activity, but recent work by Melton and colleagues [9] indicates that activln B is not expressed until the late blastula stage and activin A is only expressed from the late gastrula stage. The earlier expression of activin B causes these authors to suggest that this may be the natural inducer. However, even this activin B expression is rather late; vegetal tissue is capable of signalling at least 3 h earlier than the late-blastula stage (Jones and Woodland, Devek@aent 1987,101:557-563) and most aspects of mesoderm induction are likely to be complete by the time activin B transcription begins. The important question, therefore, is whether there is mRNA for a novel member of the activin family present in the early embryo or, alternatively, whether there is a store of maternal activin protein synthesized during oogenesis. This is being investigated in our laboratory and in others. </p><p>Members of the iibroblast growth factor (FGF) family are also believed to have a role in mesoderm induction (see [ll). Basic FGF (bFGF) is present in the egg and early embryo, although its distribution is not known, and FGF receptor protein is detectable throughout the embryo. </p><p>However, the role of bFGF in mesoderm induction is not clear, because the molecule lacks a secretion signal se- quence. Nonetheless, it is possible that other members of the FGF family, such as kFGF [ 121, are the natural in- ducing signals. We can expect more information on this in the coming year. </p><p>Mesodermal patterning Until recently, studies of mesodermal patterning have been hampered by a lack of markers. Despite the in- herent difficulties (see above), it has been necessary to use differentiated cell types as markers of dorsoven- u-al position while for the anteroposterior axis, the only marker which is exclusive to mesodenn is X&amp;OX-~, ex- pression of which is limited to posterior regions of the early embryo (Ruiz i Altaba and Melton, Development 1989,106:173183). Because there are so few anteropos- tenor mesodermal markers, and because regionalization of mesoderm and neuroectoderm along this axis appear to be closely linked, anteroposterior patterning will be discussed with neural induction. Here we concentrate on the dorsoventral axis. Previous work, discussed in [ 11, has indicated that the mesoderm-inducing signal produced by dorsovegetal blastomeres may be represented by a factor such as XTC- MIF (now known to be a homologue of activin) and that the ventrovegetal signal may be an FGF family member. This view has been reinforced by the quantitative study of Green et al. [ 131, who have compared the effects of different concentrations of XTC-MIF and bFGF on ani- mal pole tissue. They found that higher concentrations of XTC- MIF tended to induce dorsal mesodermal cell types while lower concentrations resulted in the forma- tion of ventral cell types similar to those seen in response to FGF. </p><p>This observation raised the possibility that XTC-MIF, or a similar protein, diffuses away from the vegetal hemi- sphere to form a concentration gradient. Responding cells in the animal hemisphere would then respond to diiferent concentrations of factor according to a series of thresholds (see [14]). The thresholds revealed in the original study of Green et al, were not sharp, at least partly because the animal caps used in the study were several cell layers thick, and not all the cells experienced the same concentration of factor. In later work, how- ever, animal pole cells were dispersed during a 1 h expo- sure to XTC-MIF, and then reaggregated [ 151. This proce- dure revealed remarkably sharp thresholds. For example, a twofold increase in concentration is sufficient to divert cells from expressing an epidermal keratin gene to maxi- mal expression of muscle-specihc actin. A further twofold increase causes actin expression to be switched off and expression of a neural- inducing factor to be switched on. It is possible that threshold responses of this sort underlie pattern formation in the early embryo. </p><p>Muscle-specific actin expression is a rather late marker of muscle differentiation, only switching on during gastrula- tion (Gurdon et al, Cell 1985, 41:913-922). It will there- fore be interesting to investigate threshold responses of </p></li><li><p>inductive interactions in early amphibian development New and Smith 971 </p><p>earlier markers of muscle differentiation such as MyoD [161, myogenin (Wright eta&amp; Cefl1989,56:607-617) and Myf-5 (Braun et al, EMBO J 1989, 8:701-709). The pre- diction might be that these respond to the same thresh- olds as actin as they are expressed in the same cell type. In addition it will be important to investigate other re- cently discovered mesodermal markers such as Xenopus twist, which is expressed in the notochord and lateral plate but not in the myotome [ 171, Xenopus snail, which is initially expressed in the dorsal mesoderm but then spreads laterally and ventrally [18], as well as Xbox3, the sole posterior mesodermal marker. It might then be possible to correlate the position of expression of each marker with the factor concentration required for its ex- pression. </p><p>Any model in which mesodermal patterning is specified by a gradient of an inducing factor secreted from the veg- etal hemisphere must include the recent results of Cooke [19], who used grafting techniques to change the avail- able extent of competent responding tissue in the ani- mal hemisphere. The number of cells allocated to meso- derm in these experiments depended on the number of responsive cells. Such a result would not be predicted by a simple diffusion model. Rather, it is consistent with a system in which size regulation is achieved by interac- tion between an activator and an inhibitor, such as that described by Meinbardt [ 201. Interestingly, there is some evidence for the existence of an inhibitor of mesoderm induction in the Xenopus embryo (Cooke et al, Devel- qment 1987, 101:89%908; Cooke and Smith, Da, Biol 1989, 131:383-400). </p><p>Neural induction </p><p>Little is known about the identity of neural-inducing factors. One ditficulty in designing an assay for such molecules, as previously discussed [ 11, is that more than one factor may be required. Another is that neural tissue is frequently formed by animal pole explants in response to MIPS. This is almost certainly the result of neural-induc- ing signals being formed by newly induced mesodermal cells, which then act on residual ectodermal blastomeres, rather than the direct effect of the MIFs themselves [ 151. The most dramatic example of this phenomenon may be the demonstration by Melton and colleagues [9,10] that activin (both as the pure molecule and as PIF) is able to induce abundant neural tissue, including eyes and neural tubes, from animal caps in vitro. The so-called embry- aids thus formed even appear to have an anteroposte- rior axis. Interestingly, XTC-MIF, although capable of in- ducing abundant neural tissue from responding animal caps, has not been observed to induce embryoids [ 131. The reason for this difference is not clear, but it may reflect relatively trivial differences in experimental tech- nique, such as the size of animal caps dissected. </p><p>Although little is known about the identity of the neural- inducing factors themselves, their mechanism of action, via second messengers, is being examined in some detail _. - </p><p>(reviewed in [ 11). Recent results from Otte et al [21] have demonstrated that several proteins become strongly phosphorylated after neural induction and that levels of inositol phosphates also become elevated. Their results also suggest that there are different isozymes of protein kinase C in the animal and vegetal hemispheres of the embryo. Classic work indicated that neural induction occurred ex- clusively through the radial route, with an initial induction of anterior neurectoderm followed by progressive poste- riorization under the influence of the underlying meso-...</p></li></ul>

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