Origin of abnormality in a human simelian foetus as elucidated by our knowledge of vertebrate development.

In this paper we attempt to explain the abnormality of a simelian foetus with reference to our present knowledge of vertebrate development. The various developmental defects seem to have a single common origin: the speeding-up of the progression of cell differentiation in the notochord anlage--which is the organization centre of the embryo--during the regression of the Hensen's node. Cell activity involved in the morphogenetic movements in the chordamesoderm probably stopped before it should have. The elongation of the notochord anlage was not completed, resulting in the defective development of the posterior part of the foetus. A number of pairs of posterior trunk somites were not induced. Consequently (1) the pelvic limb buds, whose posterior parts were missing, fused, bringing in further developmental deviations in the limb skeleton and abdominal muscles; (2) there are no vertebrae between the first sacral vertebra and the misshaped coccyx formed by the tail bud. The derivatives of the posterior endoderm (hindgut, bladder and ureters) were not induced either. The cauda equina is deficient. The absence of functional kidneys and the presence of embryonic urinary tubules in the pelvic cysts which are wrapped up by gut epithelium suggest the induction of the metanephric mesenchyme by ectopic endoderm. The speeding-up of differentiation in the notochord anlage also probably resulted in the excessive extension of its anterior region which is the organizer of brain structures. This explains the overdevelopment of the nose and of the neurocranium, and the low position of the ear. A gene mutation as well as a mechanical stress are the possible causes of the abnormal behaviour of the notochord anlage.

From DNA transcription to visible structure: what the development of multicellular animals teaches us.

This article is concerned with the problem of the relation between the genetic information contained in the DNA and the emergence of visible structure in multicellular animals. The answer is sought in a reappraisal of the data of experimental embryology, considering molecular, cellular and organismal aspects. The presence of specific molecules only confers a tissue identity on the cells when their concentration exceeds the 'threshold of differentiation'. When this condition is not fulfilled the activity of the genes that code for the specific molecules in question only confers on them a histogenetic potency, i.e. the capacity to form the corresponding tissue in further development (or to trans-differentiate to that tissue). The progressive restriction of histogenetic potencies during development reflects the irreversible repression of more and more genes. The establishment of a given tissue identity under the influence of an inducing tissue (or a morphogenetic hormone) is only possible when the cells have acquired the competence to respond. Tissue differentiation proceeds progressively during development thanks to the cytoplasmic 'memory' that cells retain collectively (or sometimes individually) of the items of information successively registered by their ancestors cells. The increasing complexity of visible structure emerging during development results only from the progression of tissue differentiation. This involves continual exchange of information among the cells and leads to (1) cell displacements and rearrangements, particularly during organogenesis and (2) extreme diversification of cell individualities within tissues, particularly during postembryonic growth. A mutation (just as a teratogenic factor) evokes an anomaly that is localized in both space and time because it alters a certain aspect of cell behaviour (particularly cell surface adhesiveness or mitotic activity) at the time when this is involved in the establishment of a particular structural trait. Neither the organization of the adult nor the modalities of development are encoded in the DNA. The automatic concatenation of cell interactions in the embryo and the structural amplification it entails is conditioned by the specific biochemical composition of the cytoplasm of the egg and by the heterogeneous distribution of its inclusions.

Differentiated epidermal outgrowths in the planarian Dugesia gonocephala: a model for studying cell renewal and patterning in single-layered epithelial tissue.

Large deep wounds on the ventral side of a flatworm (Planaria) will not heal. Instead, the damage to the parenchyma in the wound's roof will result in a differentiated swelling in the dorsal epidermis, above the wound which will eventually disappear with the disintegration of the underlying damaged tissue and a ventrodorsal hole appears in place of the wound. The dorsal epidermal outgrowth is formed by a number of excrescences, the development of which involves four successive stages. Their analysis suggests that epidermal cells are continuously produced by their own stem cells which remain unnoticed because their nuclei are hardly stainable. The daughter cells differentiate without information from either the underlying tissues or the basal epithelial membrane. During the first stage of this differentiation the cells become ciliated and motile, with some embryonic features. They then produce rhabdites and take up a columnar shape as they may become attached to the basal membrane. After wound setting the production of epidermal cells increases and the overcrowding of the basal membrane results in (1) detachment of stem cells and motile ciliated cells from the basal tissues, i.e. outgrowths; (2) stretching of columnar cells at the base of the outgrowths. When in the process of tissue disintegration the basal membrane of the epithelium also disappears, the cells remain in a single-layered epithelial configuration and retain their original polarity. These results are at variance with the generally accepted hypothesis that, in planarians, epidermal cells originate from the parenchyma and the epidermis is not an autonomous tissue.

The problem of automation in animal development: confrontation of the concept of cell sociology with biochemical data.

The principles of automation in animal development, as previously inferred from the concept of Cell Sociology do not fit in well with the current concept of sequential genet derepression. A more adequate explanation for those principles has been found in the literature dealing with the biochemical aspects of differentiation. Since oocytes and embryonic cells contain a greater variety of mRNAs than differentiated cells, as well as many tissue-specific (luxury) substances, it is concluded that the diversification of tissues consists of a progressive selection of specific metabolic strategies, mediated by cell-to-cell contacts, from a broad range of pre-existing strategies. For each tissue, prior to its final determination, one luxury metabolic strategy is progressively intensified and becomes dominant. The others are either suppressed or maintained as latent metabolic strategies. The latter may on occasion become dominant again (transdifferentiation). These phenomena require a theory which considers gene regulation as the activation of otherwise repressed genes by specific activator RNAs. The high (apparently maximal) transcriptional activity on the lampbrush chromosomes may represent the synthesis of all the kinds of activator RNAs which are required for the reactivation of the genes during early development. A general conception is propounded of the automatism and programming of animal development, as inferred from the confrontation of these ideas with the concept of Cell Sociology.

Cell sociology and the problem of automation in the development of pluricellular animals.

The principles of automation (automatism and programming) in the unfolding of spatiotemporal patterns during animal development are deduced from experimental data reconsidered from the point of view of cell sociology. The developmental programme in the egg is not part of the genetic information but a part of the cytoplasmic information. Throughout development cells store extra-cellular information released by their neighbours in the form of cytoplasmic information. Successive determinations cannot be considered as successive reprogrammings of cells: each one consists of a selection of one specific programme from the total information previously stored. This programme specifies cell interactions in the determined population as a whole; it is very imprecise and is progressively completed during the course of further differentiation by information released by neighbouring cell populations. Complicated patterns may emerge from only two homogeneous populations involved in distinct differentiation pathways and confronting each other. Consequently the "egg developmental programme" provides gene effectors and specific physico-chemical conditions necessary for the staring of at least two distinct differentation pathways. Experimental data suggest that there are two components in this programme. One is a molecular machinery which starts at fertilization in the whole cytoplasm. It yields two programmes of differentiation, typically first an endodermal and then an ectodermal one. The other component of the egg developmental programme, which does not require specific information, allows the interception of the first (endodermal) programme. The application of informatics to developmental automatism is discussed in the latter part of the paper.

Cell sociology and the problem of position effect: pattern formation, origin and role of gradients.

The control of pattern formation and the significance of gradients is reconsidered on the basis of the concept of cell sociology (which takes into account continuous exchange of information between cells and the possibility of autonomous progression in differentiation). Not all traits of a pattern are imposed by a single prepattern, which would be an organized molecular framework or a gradient. Patterns are unfolded in steps; these are readjustments of a cell population to intrinsic and extrinsic changes in cell activities. Prepatterns are the various components of the programme of every readjustment and are established by information of various origins, which can be dissociated experimentally: determination (elementary social prepattern), preexisting organization (antecedent pp.), surrounding cell populations (environmental pp.), position among other tissues (positional pp.) and the organization of inducers (imprinting pp.). Every transitory pattern formed during a readjustment serves as antecedent pp. during the next readjustment. Covert graded patterns result from various aspects of the social behaviour of cells (growth, aggregation, induction, cell renewal) and may serve as antecedent or imprinting prepatterns. They appear as 'water marks' in the final patterns, or generate overt graded patterns. They also manifest themselves in temporal patterns, particularly in gradients of relative growth.

Cell sociology: a way of reconsidering the current concepts of morphogenesis.

Research in the field of planarian regeneration on the one hand, and a general survey of embryology on the other, throw doubt upon the reality of supra-cellular controls, which are still at the basis of all modern concepts of morphogenesis. The necessity of referring to such controls, which have never been convincingly demonstrated, is probably due to the fact that two aspects of cell behaviour have been underestimated: 1) the capacity of cells to change their individualities for a time independently of other cells; 2) the social behaviour of cells, which is the consequence of the reciprocal exchange of information. Pattern formation and pattern remodeling in normal development results from readjustments of cell populations to local or global changes. The common specific syntheses and cell migration. In the young embryo these may promptly restore the unity of the injured primordium, leading to so-called restitution; this is based on a normal sequence of further readjustments in the primordium. In older organisms the same responses give rise to cell interactions which may be the starting point for further sequential readjustments (regeneration)--in some instances these are comparable to those that originally organized the primordium in question during development. The desirability of giving up the notion of morphogenetic field is discussed.

Symptoms and causation of the planarian disease related to cancer.

The disease provoked by injections of water and other harmless liquids or wounds without tissue loss, is characterized by the regression of certain organs, opening in the epidermis, pigmentary anomalies and malignant tumors. The very few worms which recover spontaneously, regenerate the eliminated parts or develop supernumerary structures. Wound are producing the disease less frequently when planarians are undernourished. The disease can also manifest itself spontaneously, especially in the summer. Diseased worms become unable to regenerate. During a transitory period epimorphosis is still possible but is not followed by morphallaxis. The symptoms of the disease manifest themselves in the regenerated parts. A fragment cut out from a worm that just became diseased regenerates and recovers completely. The results give additional evidence to the earlier conclusions about the "type I cell" system of planarians. The disease is provoked by an excessive activity of this system with respect to the animal's actual need and is analogous both to cancer and the consequences of X-ray treatment.