Monod, Jacob, Lwolf: Nobel Prize Lectures

Date:
1966-1970
Reference:
PP/CRI/H/3/5/4
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Licence: In copyright

Credit: Monod, Jacob, Lwolf: Nobel Prize Lectures. Source: Wellcome Collection.

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    arrangement of the elements of the limb skeleton in terms of perhaps quite simple mechanical forces governing the way in which the proliferative zone varies the spatial distributions of newly added cells and so dictates the sites of future cartilage condensations. In basic outline the skeletal elements of the vertebrate limb are arranged so that at increasingly distal levels there is a duplication of elements for each element already formed more proximally. This pattern of development could be explained if the proliferative zone were morphogenetically disposed in such a way that, as it lays down new cells which will form successively more distal limb parts, it concentrates them towards the forward and rear borders of each cartilage rudiment which is already in process of differentiation proximal to it. The simpler non-duplicating succession of elements formed in the digits might reflect modified morphogenetic circumstances affecting the proliferative zone at later stages of development. In addition to the formation of cartilage the single mesodermal cell type can freely differentiate into a number of adult cell types, -some of which may themselves be able to undergo transforma tion of type 136]. Transformations such as ossification of cartilage occur according to internally generated circumstances, including mechanical circumstances [31], so that mesoderm on its own can generate considerable complexity of arrangement of a number of cell types. As a result of this arrangement the mesoderm can directly control the development of hairs, feathers, scales, claws and nails which are formed later in development by multipotent ectoderm under the inductive influence of specific components of the mesoderm 129]. Additional anatomical complexity is generated by the superimposition of patterns of invading cell types such as muscle, blood vessels, neural crest and nerve fibres. Their dis tributions and the results of their inductive effects in the limb can also be determined by mechanical conditions created autonomously by the mesoderm. This example illustrates how an organ of considerable anatomical complexity can be formed simply by the control of the distribution of multipotent embryonic cells without otherwise requiring more than a number of inbuilt, fixed rules for the induction of the contributing cell types. In this case (like many others—for example, the cranio-caudal sequence of formation of the neural plate—where patterns of differentiation may appear to change according to their times of origin), it can be shown that there is no change as time passes in the developmental rules operating. There is direct evidence that apical cells retain constant potentialities at each stage of outgrowth (Fig. 3.6.12B). Any changes in their products in time must therefore be due to progressively changing cues, either inductive or morphogenetic, from more proximal limb parts in process of differentiating. Clearly the final adult structure of any complex organ which, like the limb, is composed of a number of different specialized cell types will not only reflect the inductive effects of these cells but also interactions between them resulting from the anatomical and physiological properties which characterize the cells once they begin to differentiate. Differentiated cells display a bewildering variety of highly specific and adaptive potentialities to respond to circumstances including, for example, trophic dependence on other cells [30] and responsiveness to mechanical stresses [31], to metabolic conditions [32] or to nerve impulse patterns [33]. As part of their states of developmental specializations, some cells may synthesize hormone receptors whose activation by a hormone can be used to regulate their rates of mitosis and differentiation [34], or even, as in the case of withdrawal of the tail at metamorphosis in amphibian tadpoles, rates of selective cell death (Chapter 4.4). The differences in the reproductive systems in the two sexes in vertebrates, which are due to hormonally induced differential development in initially identical embryonic tissues, illustrates the potency of such mechanisms in bringing about variations in adult anatomy. In this way the details of adult anatomy can become highly adapted to their functions. Anatomical complexity generated in this way as a secondary consequence of properties of the differentiated states of cells, clearly does not add to the complexity of embryological control mechanisms required. These mechanisms have merely to be sufficient to generate the basic types of specialized cells in the first place. The states of embryonic cells prior to the initiation of differentiation by induction If we trace the sources of the multipotent cells involved in various inductions it emerges that they are derived from a population of cells which, judging by their unchanging appearance and consistent anatomical location, may serve continuously throughout development as a reservoir of stem cells which remain free of any restriction in their potentialities. Thus organs formed at the neurula stage (Fig. 3.6.8) are all formed from multipotent cells from the ectoderm which is made up of cells derived, without any apparent anatomical modification, directly from the external cells of the blastula. Even organs which are only formed towards the end of development, such as hairs and claws, are induced from multipotent cells of the stratum germinativum of the epidermis which itself is anatomically the direct descendent of the ectoderm. These considerations raise the possibility that this multipotent cell population may simply owe its properties to the fact that its cells are unchanged from the totipotent cells of the blastula. Further light on the persistence in fully developed tissues of cells with high degrees of multipotency comes from the phenomenon of regeneration. The regeneration of the vertebrate limb (Fig. 3.6.13) restores the spatial layout of specialized structures which was achieved during embryogenesis by means
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