Collective specification of cellular development

Studies of chimeras and in vivo development demonstrate that cell lineages are often quite variable, apparently in response to chance perturbations. This points to an apparent contradiction: although individual cells are the units of genetic information and differentiation, not all cellular events need be precise for the development of functional organisms. The social organization of ants can serve as a metaphor that helps understand the mechanisms that underlie such development. Ants suggest that continued cellular interactions and environmental conditions could specify the proportion and general location of specialized units. Leaf venation is used as a concrete example of this general principle. A signal produced continuously by all cells specifies a requirement for vein differentiation. The cells that respond by differentiation then transport the signal away from the leaf; this removal acting as a feedback indicating that the requirement is being met. Because transport increases during vein differentiation, early initiation occurs in excess and vein 'competition' for the signal assures an acceptable outcome. Such specification would be robust since it does not depend on events in any single cell, and chance events, rather than being corrected or reversed, may be built upon in reaching an expected, collective phenotype. The absence of detailed information preceding development distinguishes this hypothesis from the common alternatives of a program or blueprint. Collective specification would have important implications for developmental plasticity and evolution.     

Heterocyst differentiation and pattern formation in cyanobacteria: a chorus of signals

Heterocyst differentiation in filamentous cyanobacteria provides an excellent prokaryotic model for studying multicellular behaviour and pattern formation. In Anabaena sp. strain PCC 7120, for example, 5-10% of the cells along each filament are induced, when deprived of combined nitrogen, to differentiate into heterocysts. Heterocysts are specialized in the fixation of N(2) under oxic conditions and are semi-regularly spaced among vegetative cells. This developmental programme leads to spatial separation of oxygen-sensitive nitrogen fixation (by heterocysts) and oxygen-producing photosynthesis (by vegetative cells). The interdependence between these two cell types ensures filament growth under conditions of combined-nitrogen limitation. Multiple signals have recently been identified as necessary for the initiation of heterocyst differentiation, the formation of the heterocyst pattern and pattern maintenance. The Krebs cycle metabolite 2-oxoglutarate (2-OG) serves as a signal of nitrogen deprivation. Accumulation of a non-metabolizable analogue of 2-OG triggers the complex developmental process of heterocyst differentiation. Once heterocyst development has been initiated, interactions among the various components involved in heterocyst differentiation determine the developmental fate of each cell. The free calcium concentration is crucial to heterocyst differentiation. Lateral diffusion of the PatS peptide or a derivative of it from a developing cell may inhibit the differentiation of neighbouring cells. HetR, a protease showing DNA-binding activity, is crucial to heterocyst differentiation and appears to be the central processor of various early signals involved in the developmental process. How the various signalling pathways are integrated and used to control heterocyst differentiation processes is a challenging question that still remains to be elucidated.     

Surviving Drosophila eye development

During eye development, cell death interplays dynamically with events of differentiation to achieve the remarkably patterned structure of the fly compound eye. Mutations in genes that affect the normal developmental process can lead to excessive death of progenitor cells, or, alternatively, to the differentiation of supernumerary neurons, pigment and cone cells due to survival of cells that would normally be eliminated. These data reveal that eye development contains cell selection processes: only certain cells are selected to undergo differentiation, and supernumerary cells are actively eliminated by cell death pathways to achieve the highly ordered lattice of the eye. The final number of cells that comprise the eye is controlled through a balance of cell proliferation with proper cell differentiation and removal by cell death.     

Biological evolution as an expression of body-plan potentialities.

A growing bulk of recent data from different fields as molecular biology, developmental biology, genetics, paleontology and phylogenetics shows that organisms play a more active role in their evolution than what postulated by the random variation-natural selection paradigm of the neo-Darwinian synthesis. Organisms show during development and morphogenesis autopoietic processes which are related to their body-plan potentialities. These potentialities are expressed through regulatory networks in which a plastic genome participates together with proteins and other substances in an epigenetic space. The epigenetic systems which arise from this interaction may be inherited and then assume a significant role in evolution becoming the source of new acquired characters. The acquisition of new traits through the epigenetic systems is influenced directly by environmental cues. If this process is coherent with the environmental demands it co-operates with natural selection in organism adaptation. An outstanding role in this context may be played by phenotypic plasticity if, as emerges in recent views, it may constitute a general basis for genetic assimilation processes.     

Population structure and evolutionary progress

Wright's shifting-balance theory is discussed as an example of a process that can cause species to evolve combinations of characters that could not evolve under natural selection alone. A review of the existing theory of peak shifts indicates that the conditions of extreme isolation that are necessary to permit genetic drift to alter the outcome of natural selection in local populations would make gene flow too weak to spread a new combination of genes to other populations in a reasonable time. Instead, it seems likely that major demographic changes must occur in a species for the shifting-balance process to work. A discussion of direct and indirect studies of gene flow in natural populations suggests that the current genetic structure of many species is likely to reflect past demographic events rather than ongoing gene flow. It is possible then that demographic processes could be responsible for spreading new traits in a species, but that would be true whether those new traits evolved only owing to natural selection or owing in addition to genetic drift and other forces.     

Sugars as signal molecules in plant seed development.

Higher plants as sessile organisms react very flexible to environmental changes and stresses and use metabolites like glucose, sucrose and nitrate not only as nutrients but also as signals as part of their life strategies. The role of metabolites as signal molecules has attracted considerable interest during recent years. Data reviewed here for developing plant seeds suggest a trigger function of especially sugars also in development in that metabolic regulatory control can override developmental regulation, i.e., the developmental programme only continues normally if a certain metabolic state is sensed at a given time point in a given cell or tissue. Several experimental strategies have provided mainly correlative evidence that certain sugar levels and/or the resulting changes in osmotic values are necessary within defined tissues or cells to maintain a distinct stage of differentiation or to proceed with the developmental programme. In young legume seeds, but certainly also in other tissues, a high hexose (probably mainly glucose) level seems to maintain the capacity of cells to divide whereas - later in seed development - a certain sucrose level is necessary to induce storage-associated cell differentiation. A major determinant of embryo hexose levels in young legume seeds is an apoplastic invertase preferentially expressed in the inner cell layers of the seed coat. The enzyme cleaves the incoming photoassimilate sucrose into glucose and fructose. During development the tissue harbouring the invertase is degraded in a very specific spatial and temporal pattern as part of the developmental programme and is thus creating steep glucose gradients within the cotyledons. These gradients can be measured at nearly cellular resolution and were found to be correlated positively with cell division rate and negatively with cell differentiation and storage activities. A hexose and a sucrose transporter accumulating only in the epidermal cell layer of the cotyledons seem to be essential in creating and maintaining these gradients. To gain further insights into the role of metabolites, especially sugars, as triggers of developmental processes we foremost have to identify receptor molecules already characterised in yeast, and to describe and understand the signal transduction networks involved.     

Condition-dependent asymmetry is fluctuating asymmetry

Asymmetry has been demonstrated to play a role in signalling systems such as sexual selection and pollination, with receivers showing a preference for symmetrical signals. Large signals often have the smallest degree of asymmetry, a finding that is consistent with signal asymmetry being condition-dependent. The kind of asymmetry displayed by signals was supposed or shown to be fluctuating asymmetry, and signals revealing individual differences in the ability to stabilize developmental processes, despite a hostile developmental environment, was supposed to be the basis for the preference for symmetric signals. Recently, it has been suggested that condition-dependent signals display antisymmetry rather than fluctuating asymmetry, based on analyses of the relationship between asymmetry and mean length of the left and the right character in a few published graphs of absolute asymmetry of signals. Here I demonstrate on the basis of a much larger number of data sets, including those previously published, that the previous results are biased because of the methods used for the analyses, and that characters with condition-dependent asymmetry show fluctuating asymmetry rather than antisymmetry. In particular, frequency distributions of signed left-minus-right character values display leptokurtosis, as predicted if asymmetry distributions reflected individual differences in developmental precision, rather than platykurtosis. Platykurtosis is predicted if the traits are antisymmetric. The preponderance of leptokurtic distributions is consistent with recent modelling showing that inherent differences in the ability of individuals to control developmental processes invariably leads to leptokurtic distributions of signed left-minus-right character values.     

Sensing cellular states—signaling to chromatin pathways targeting Polycomb and Trithorax group function

Cells respond to extra- and intra-cellular signals by dynamically changing their gene expression patterns. After termination of the original signal, new expression patterns are maintained by epigenetic DNA and histone modifications. This represents a powerful mechanism that enables long-term phenotypic adaptation to transient signals. Adaptation of epigenetic landscapes is important for mediating cellular differentiation during development and allows adjustment to altered environmental conditions throughout life. Work over the last decade has begun to elucidate the way that extra- and intra-cellular signals lead to changes in gene expression patterns by directly modulating the function of chromatin-associated proteins. Here, we review key signaling-to-chromatin pathways that are specifically thought to target Polycomb and Trithorax group complexes, a classic example of epigenetically acting gene silencers and activators important in development, stem cell differentiation and cancer. We discuss the influence that signals triggered by kinase cascades, metabolic fluctuations and cell-cycle dynamics have on the function of these protein complexes. Further investigation into these pathways will be important for understanding the mechanisms that maintain epigenetic stability and those that promote epigenetic plasticity.     

Moss systems biology en route: phytohormones in Physcomitrella development

The moss Physcomitrella patens has become a powerful model system in modern plant biology. Highly standardized cell culture techniques, as well as the necessary tools for computational biology, functional genomics and proteomics have been established. Large EST collections are available and the complete moss genome will be released soon. A simple body plan and the small number of different cell types in Physcomitrella facilitate the study of developmental processes. In the filamentous juvenile moss tissue, developmental decisions rely on the differentiation of single cells. Developmental steps are controlled by distinct phytohormones and integration of environmental signals. Especially the phytohormones auxin, cytokinin, and abscisic acid have distinct effects on early moss development. In this article, we review current knowledge about phytohormone influences on early moss development in an attempt to fully unravel the complex regulatory signal transduction networks underlying the developmental decisions of single plant cells in a holistic systems biology approach.     

Developmental stability,sexual selection and speciation

Fluctuating asymmetry occurs when an individual is unable to undergo identical development of an otherwise bilaterally symmetric trait on both sides of its body. Since both sides of a bilaterally symmetric trait are the result of the actions of a single genome, fluctuating asymmetry represents an epigenetic measure of the sensitivity of development to stress. Different morphological traits may show a direct relationship between their functional importance and their degree of developmental canalization. This may explain why some characters show high degrees of fluctuating asymmetry, and why these characters more often become exaggerated secondary sexual ornaments. The degree of fluctuating asymmetry is generally larger in small marginal populations living in novel environments, and this will particularly lead to relatively large degrees of asymmetry in the least developmentally canalized traits. More stringent selection against heterozygotes in marginal populations may further break down developmental stability and linkage groups which would lead to increased genetic variance. Females may prefer to mate with males having large, but relatively symmetric morphological characters, because it is more difficult to make large traits (a good genes argument), a large trait is more easily perceived (a sensory bias preference), and because symmetry signals ability to cope with stress (a good genes argument). The low degree of developmental stability and the large amount of genetic variance in secondary sexual characters in small, marginal populations could set the scene for rapid development of divergence and speciation in marginal populations.     

Brain evolution and development: adaptation,allometry and constraint

Phenotypic traits are products of two processes: evolution and development. But how do these processes combine to produce integrated phenotypes? Comparative studies identify consistent patterns of covariation, or allometries, between brain and body size, and between brain components, indicating the presence of significant constraints limiting independent evolution of separate parts. These constraints are poorly understood, but in principle could be either developmental or functional. The developmental constraints hypothesis suggests that individual components (brain and body size, or individual brain components) tend to evolve together because natural selection operates on relatively simple developmental mechanisms that affect the growth of all parts in a concerted manner. The functional constraints hypothesis suggests that correlated change reflects the action of selection on distributed functional systems connecting the different sub-components, predicting more complex patterns of mosaic change at the level of the functional systems and more complex genetic and developmental mechanisms. These hypotheses are not mutually exclusive but make different predictions. We review recent genetic and neurodevelopmental evidence, concluding that functional rather than developmental constraints are the main cause of the observed patterns.     

COMPOSITE TRAITS,SELECTION RESPONSE,AND EVOLUTION

It is very difficult to relate macroevolutionary patterns to the microevolutionary processes described by quantitative-genetic models. Quantitative-genetic parameters are statistical abstractions. Their long-term significance and evolution might be understood if they can be related to development, physiology, and other biological properties. Most continuous traits are composites of other traits that may contribute differentially to selection response and long-term divergence. The operation of selection on continuous traits can be indirect, with intermediate optima caused by correlated fitness components. Few realistic models are available, and heritable maternal effects can further complicate selection response. Examples involving allometry of brain and body size in mammals suggest that prenatal and postnatal growth have contributed differently to body-size evolution, with different correlated changes in brain size. Several different models could explain these patterns, and interpretation is further complicated by statistical difficulties in comparative biology. Quantitative-genetic models may become more informative and predictive if variation in their parameters can be explained by developmental and other biological processes that have been shaped by the previous history of the population.     

Irreversible barrier to the reprogramming of donor cells in cloning with mouse embryos and embryonic stem cells

Somatic cloning does not always result in ontogeny in mammals, and development is often associated with various abnormalities and embryo loss with a high frequency. This is considered to be due to aberrant gene expression resulting from epigenetic reprogramming errors. However, a fundamental question in this context is whether the developmental abnormalities reported to date are specific to somatic cloning. The aim of this study was to determine the stage of nuclear differentiation during development that leads to developmental abnormalities associated with embryo cloning. In order to address this issue, we reconstructed cloned embryos using four- and eight-cell embryos, morula embryos, inner cell mass (ICM) cells, and embryonic stem cells as donor nuclei and determined the occurrence of abnormalities such as developmental arrest and placentomegaly, which are common characteristics of all mouse somatic cell clones. The present analysis revealed that an acute decline in the full-term developmental competence of cloned embryos occurred with the use of four- and eight-cell donor nuclei (22.7% vs. 1.8%) in cases of standard embryo cloning and with morula and ICM donor nuclei (11.4% vs. 6.6%) in serial nuclear transfer. Histological observation showed abnormal differentiation and proliferation of trophoblastic giant cells in the placentae of cloned concepti derived from four-cell to ICM cell donor nuclei. Enlargement of placenta along with excessive proliferation of the spongiotrophoblast layer and glycogen cells was observed in the clones derived from morula embryos and ICM cells. These results revealed that irreversible epigenetic events had already started to occur at the four-cell stage. In addition, the expression of genes involved in placentomegaly is regulated at the blastocyst stage by irreversible epigenetic events, and it could not be reprogrammed by the fusion of nuclei with unfertilized oocytes. Hence, developmental abnormalities such as placentomegaly as well as embryo loss during development may occur even in cloned embryos reconstructed with nuclei from preimplantation-stage embryos, and these abnormalities are not specific to somatic cloning.     

Phenotypic integration and independence: Hormones, performance, and response to environmental change

Hormones coordinate the co-expression of behavioral, physiological, and morphological traits, giving rise to correlations among traits and organisms whose parts work well together. This article considers the implications of these hormonal correlations with respect to the evolution of hormone-mediated traits. Such traits can evolve owing to changes in hormone secretion, hormonal affinity for carrier proteins, rates of degradation and conversion, and interaction with target tissues to name a few. Critically, however, we know very little about whether these changes occur independently or in tandem, and thus whether hormones promote the evolution of tight phenotypic integration or readily allow the parts of the phenotype to evolve independently. For example, when selection favors a change in expression of hormonally mediated characters, is that alteration likely to come about through changes in hormone secretion (signal strength), changes in response to a fixed level of secretion (sensitivity of target tissues), or both? At one extreme, if the phenotype is tightly integrated and only the signal responds via selection's action on one or more hormonally mediated traits, adaptive modification may be constrained by past selection for phenotypic integration. Alternatively, response to selection may be facilitated if multivariate selection favors new combinations that can be easily achieved by a change in signal strength. On the other hand, if individual target tissues readily "unplug" from a hormone signal in response to selection, then the phenotype may be seen as a loose confederation that responds on a trait-by-trait basis, easily allowing adaptive modification, although perhaps more slowly than if signal variation were the primary mode of evolutionary response. Studies reviewed here and questions for future research address the relative importance of integration and independence by comparing sexes, individuals, and populations. Most attention is devoted to the hormone testosterone (T) and a songbird species, the dark-eyed junco (Junco hyemalis).     

Decision-making by the immune response

Decisions by uncommitted cells to differentiate down one lineage pathway or another is fundamental to developmental biology. In the immune system, lymphocyte precursors commit to T- or B-cell lineages and T-cell precursors to CD4 or CD8 independently of foreign antigen. T and B cells must also decide whether or not to respond to antigen and when a response is initiated, what sort of response to make such as the type of antibody, CD4 or CD8, and CD4 Th1 or Th2. The two basic mechanisms for these decision-making processes are selection and instruction. Selection depends on prior stochastic production of precommitted cells, which are then selected to respond by an appropriate signal; for example, CD8 and CD4 responses selected by peptide presented in association with major histocompatibility complex class I or II. In contrast, instruction occurs when an uncommitted precursor embarks upon a differentiation pathway in response to a particular set of signals; for example, Th1 and Th2 lineage commitment. In this paper, the signals that determine Th1 and Th2 differentiation are examined with a mathematical model and shown to act as a bistable switch permitting either Tbet or Gata3 to be expressed in an individual cell but not both. The model is used to show how the Tbet Gata3 network within an individual cell interacts with cytokine signals between cells and suggests how Th1 and Th2 lineage commitment can become irreversible. These considerations provide an example of how mathematical models can be used to gain a better understanding of lymphocyte differentiation in an immune response.