A demonstration of pattern formation without positional information in Dictyostelium

Although positional information, conveyed by morphogen gradients, is a widely accepted way of forming patterns during development, an alternative method is conceivable, based on the intermingled differentiation of cells with different fates, followed by their sorting into discrete pattern elements. It has been proposed that Dictyostelium prestalk and prespore cells behave in this way at the mound stage of development. However, it has been difficult to conclusively demonstrate that they initially differentiate intermingled, because rapid cell movement within the mound makes it impossible to be sure where prestalk and prespore cells originate. We have taken a novel approach to address this problem by blocking cell movement at different stages in development, using the actin-depolymerizing drug, latrunculin-A. Prestalk and prespore cells differentiate with essentially normal efficiency and timing in such paralyzed structures. When movement is blocked sufficiently early, the major cell types all subsequently differentiate at scattered positions throughout the aggregate, and even in the streams leading into it. Our work strongly supports the idea that the prestalk/prespore pattern in Dictyostelium forms without positional information and demonstrate that latrunculin-A may provide a useful tool for the investigation of patterning in other organisms.     

A theory of biological pattern formation

One of the elementary processes in morphogenesis is the formation of a spatial pattern of tissue structures, starting from almost homogeneous tissue. It will be shown that relatively simple molecular mechanisms based on auto- and cross catalysis can account for a primary pattern of morphogens to determine pattern formation of the tissue. The theory is based on short range activation, long range inhibition, and a distinction between activator and inhibitor concentrations on one hand, and the densities of their sources on the other. While source density is expected to change slowly, e.g. as an effect of cell differentiation, the concentration of activators and inhibitors can change rapidly to establish the primary pattern; this results from auto- and cross catalytic effects on the sources, spreading by diffusion or other mechanisms, and degradation.Employing an approximative equation, a criterium is derived for models, which lead to a striking pattern, starting from an even distribution of morphogens, and assuming a shallow source gradient. The polarity of the pattern depends on the direction of the source gradient, but can be rather independent of other features of source distribution. Models are proposed which explain size regulation (constant proportion of the parts of the pattern irrespective of total size). Depending on the choice of constants, aperiodic patterns, implying a one-to-one correlation between morphogen concentration and position in the tissue, or nearly periodic patterns can be obtained. The theory can be applied not only to multicellular tissues, but also to intracellular differentiation, e.g. of polar cells.The theory permits various molecular interpretations. One of the simplest models involves bimolecular activation and monomolecular inhibition. Source gradients may be substituted by, or added to, sink gradients, e.g. of degrading enzymes. Inhibitors can be substituted by substances required for, and depleted by activation.Sources may be either synthesizing systems or particulate structures releasing activators and inhibitors.Calculations by computer are presented to exemplify the main features of the theory proposed. The theory is applied to quantitative data on hydra — a suitable one-dimensional model for pattern formation — and is shown to account for activation and inhibition of secondary head formation.     

Hutterite belief in evil eye: Beyond paranoia and towards a general theory of invidia

Most studies of evil eye link economic and political inequality to the fear of appropriation of property while tying envy (invidia) to paranoia. In both psychiatric and anthropological studies of evil eye, explanation of the phenomenon is problematic because the data are retroductive — involving a rationalization on the part of the patient or informant in terms of either delusions or world-view respectively. In this paper the connection between invidia and paranoia is questioned by grounding the analysis of Hutterian beliefs in evil eye in social interaction rather than retroductive explanation. In the case of the Hutterites it is envy itself which is feared and linked to high anxiety levels and sometimes to anxiety attacks or even depression.     

Taste cell responses in the polyphagous arctiid, Grammia geneura: towards a general pattern for caterpillars

The caterpillars of Grammia geneura are polyphagous as individuals. Electrophysiological responses of its medial and lateral galeal styloconic sensilla to 21 amino acids, 6 carbohydrates, 10 chemically diverse plant secondary compounds and two inorganic salts were examined. In the medial sensillum, a single cell responded to 8 amino acids, 3 carbohydrates, and the iridoid, catalpol, which is present in a favored hostplant. In the lateral sensillum, one cell responded to amino acids and another to fructose. Two cells in each sensillum responded to secondary compounds and it is suggested that the same cells are stimulated by inorganic salts. There was no evidence of a separate salt-sensitive cell. Phenylalanine stimulated a deterrent cell in the medial sensillum and was behaviorally deterrent. Some essential amino acids did not stimulate any cells and it is suggested that a small number of amino acids (sometimes non-essential) may serve as indicators of nutrient quality. Sugars probably serve as the primary phagostimulants because they are in relatively high concentrations in plants. It is proposed that taste receptor cells should be categorized primarily by their behavioral effects as phagostimulatory or deterrent, rather than their specific ranges of responsiveness. This would emphasize the basic similarities across taxa.     

Synapse formation by sensory neurons after cross-species transplantation in crickets: the role of positional information

The role of positional information in synapse formation was studied in the cricket cercal sensory system by transplanting epidermis from one species of cricket to another. Strips of cercal epidermis containing identified sensory neurons were transplanted from a black donor species to a tan host species; the color difference was used to distinguish between donor and host tissue in adults. Transplanted sensory neurons regenerated axons into the host terminal abdominal ganglion where they formed functional chimeric synapses. These methods were used to test the role of positional information in central synapse formation. Newly generated sensory neurons, formed by the donor tissue at the border between graft and host, were examined to test the idea that their position would determine their structure, function, and projection pattern. These "intercalated" sensory neurons support the positional information hypothesis. First, they had directional sensitivities which were appropriate to their location on the cercus; receptors of this directionality would never be made by the donor tissue if left in its original position. Second, these sensory neurons projected to regions of the CNS known to be appropriate for their directionality. Finally, simultaneous recordings from these ectopic sensory neurons and host interneurons demonstrated the expected synaptic connection, based on the overlap of pre- and postsynaptic cells. Thus three aspects of receptor function, directionality, afferent projection, and choice of synaptic partners, appeared to be controlled by positional information.     

Mathematics and biology: a Kantian view on the history of pattern formation theory

Driesch's statement, made around 1900, that the physics and chemistry of his day were unable to explain self-regulation during embryogenesis was correct and could be extended until the year 1972. The emergence of theories of self-organisation required progress in several areas including chemistry, physics, computing and cybernetics. Two parallel lines of development can be distinguished which both culminated in the early 1970s. Firstly, physicochemical theories of self-organisation arose from theoretical (Lotka 1910-1920) and experimental work (Bray 1920; Belousov 1951) on chemical oscillations. However, this research area gained broader acceptance only after thermodynamics was extended to systems far from equilibrium (1922-1967) and the mechanism of the prime example for a chemical oscillator, the Belousov-Zhabotinski reaction, was deciphered in the early 1970s. Secondly, biological theories of self-organisation were rooted in the intellectual environment of artificial intelligence and cybernetics. Turing wrote his The chemical basis of morphogenesis (1952) after working on the construction of one of the first electronic computers. Likewise, Gierer and Meinhardt's theory of local activation and lateral inhibition (1972) was influenced by ideas from cybernetics. The Gierer-Meinhardt theory provided an explanation for the first time of both spontaneous formation of spatial order and of self-regulation that proved to be extremely successful in elucidating a wide range of patterning processes. With the advent of developmental genetics in the 1980s, detailed molecular and functional data became available for complex developmental processes, allowing a new generation of data-driven theoretical approaches. Three examples of such approaches will be discussed. The successes and limitations of mathematical pattern formation theory throughout its history suggest a picture of the organism, which has structural similarity to views of the organic world held by the philosopher Immanuel Kant at the end of the eighteenth century.     

Evidence that positional information is used to establish the prestalk-prespore pattern in Dictyostelium discoideum aggregates

Two contrasting mechanisms have been proposed for the establishment of the prestalk-prespore pattern in the multicellular aggregate of the simple eukaryote Dictyostelium discoideum. One involves intermingled, non-position-dependent cell differentiation followed by sorting out which produces the pattern of prestalk cells in the anterior region and prespore cells posteriorly. The second mechanism involves patterning according to the position of cells within the aggregate, in which case intermingled cell types are not expected. Here we use a monoclonal antibody (MUD1), recognising a prespore cell surface antigen, to study the initial appearance of prespore cells in aggregates. Quantitative studies were made with a flow cytometer and frozen sections were used to localise the cells expressing the prespore antigen. This antigen first appeared at the onset of tip formation in the centre of aggregates in a position-dependent fashion. The prespore antigen was not detected in the tip region or in streams of cells entering the aggregate. We re-examined the evidence on which the non-position-dependent differentiation model is based. Our results support the positional model for pattern formation.     

Evolution of structure and information processing in the nervous system: Part IV of a general theory

Starting from fundamental principles, evolution of the nervous system is modelled as a random walk process in a multidimensional representation space (the F-space). This space is not flat, it is highly structured in terms of step probability. Fundamental considerations of evolutionary speed, efficiency of information processing, and priorities lead to specific theoretical predictions of the most probable pathways of evolution of the nervous system and its mechanisms of information processing. These processes are represented as vector paths (F-paths) in the F-space. Cognition becomes a process of correlations of the input signal to information stored in memories. Higher level brain processes involve extrapolation and interpolation along F-paths, input data reduction by clearly specifiable abstraction methods, and a unique process using abstracted analogs. These processes define and limit what the brain does and how it can do it. These considerations lead to certain inevitable conclusions (consequences of the fundamental principles) for the basis of our logical reasoning, decision-making, the process of dreaming (conscious and sleep), and explicit definitions of consciousness, unconsciousness, and personality. Detailed applications of this theory for analyzing empirical findings are suggested in the final paragraphs.     

Evolution: towards a genetical theory of adaptation

The population genetic basis for adaptation has remained obscure despite a longstanding body of theory. Microbial selection experiments are beginning to provide some answers.     

On the role of gravity and positional information in embryological axis formation and tissue compartmentalization

The idea that gravity affects dorso-ventral polarization in anouran development contrasts with the theories of self-organization through reaction-diffusion processes. As a result of a literature study we discuss the role of gravity in embryological axis formation and speculate on an influence of gravity on tissue compartmentalization. The involvement of compartmentalization in tissue homeostasis is discussed in the light of the recent progress in mammalian cell culture studies.     

Robust development as a consequence of generated positional information

The origin and robustness of morphogenesis are studied by dynamical system modeling of a cell society, in which cells possessing internal chemical reaction dynamics interact with each other through their mutual interaction with diffusive chemicals in a two-dimensional medium. It is found that stem-type cells differentiate into various cell types (where a cell 'type' is defined by a type of intra-cellular dynamics) due to a dynamic instability caused by cell-cell interactions in a manner described by the isologous diversification theory. The differentiations are spatially regulated by the concentration of chemicals in the medium, while the chemical concentrations are locally influenced by the intra-cell dynamics. Through this reciprocal relationship, chemical concentrations come to exhibit spatial variation as differentiated cell types begin to emerge, and as a result the regulation exercised by the chemical concentrations become spatially inhomogeneous. This reinforces the process of differentiation, through which spatial patterns of differentiated cells appear. Within this reciprocal relationship, the concentration gradients are read and interpreted by the cell as positional information. A spatial order of cells realized in this process represents a stable state of the system governed by this reciprocal relationship, and that the developmental process through which this state is realized is robust with respect to perturbations. The dependence of the morphogenesis on history and the community effect in cell differentiation are also discussed.     

Problems and paradigms: Molecular problems of positional information

Enough is known about pattern formation in development to encourage investigations at the molecular level. A pressing need is to understand the molecular basis of positional value, which is similar to determination. It is suggested here that there is a molecular entity which varies in such a way that it corresponds with cell position. Other problems in pattern formation include thresholds, identification of morphogens, and the origin of handedness.     

Using information from asthma patients: a trial of information feedback in primary care.

OBJECTIVE--To test the effects of feedback of information about patients'' asthma to primary care teams. DESIGN--Patients'' reports of morbidity, use of health services, and drug use on questionnaire was given to primary care teams. Randomised controlled trial with general practices as the subject of the intervention was used to test effectiveness of supplying information. SETTING--Primary care in district health authority, London. SUBJECTS--23 general practices, each of which notified at least 20 asthmatic patients aged 15-60 years for each principal. Practices were randomly allocated to an invention group (receiving feedback of information on control of asthma) or a control group (no feedback). INTERVENTION--Information on cards inserted in patients'' medical records; booklet copies of information for team members; formal presentation to primary care teams; poster displays of data on patients in each practice. MAIN OUTCOME MEASURES--Type and frequency of asthma symptoms, use of health services, use of asthma drugs. RESULTS--Reported morbidity at entry to the study was substantial: 45% (818) patients reported breathlessness at least once a week. Less than half these patients were using inhaled steroids regularly. Intervention and control groups did not differ in practice or patient characteristics on entry to the study. In spite of the potential for improvement no differences were observed between the two practice groups at the end of the study--for example, breathlessness at least once a week in last six months was experienced by 36% in intervention group v 35% in control group (t = -0.27, P < 0.79); surgery attendance in last six months by 48% v 48% (t = -0.05, P < 0.96); regular use of inhaled steroids by 60% v 58% (t = 0.51, P < 0.62). CONCLUSION--Feedback to general practitioners of information about patients'' asthma does not on its own lead to change in the outcome of clinical care.     

Specifying positional information in the embryo: looking beyond morphogens

Concentration gradients of small diffusible molecules called morphogens are key regulators of development, specifying position during pattern formation in the embryo. It is now becoming clear that additional or alternative mechanisms involving interactions among cells are also crucial for positional specification.