Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas

Despite the pivotal role of the pancreas in hormonally-regulated pathways in the body, e.g. glucose homeostasis, the genetic mechanisms defining it have for many years remained largely enigmatic. After years out of the spotlight, pancreas development has once again come to centre stage. To a large extent, this is due to recent advances made through the detailed analysis of transgenic mice which have been engineered to carry mutations in specific developmental control genes. This review specifically focuses on the specification of the endocrine pancreas lineage and in particular on the role of the developmental control genes Pax4 and Pax6 in the generation of specific endocrine cell types. The comparison of various phenotypes of different mouse mutants affecting endocrine development supports a model in which Pax4 and Pax6 are required for the differentiation of certain endocrine cell lineages and implies a potential for acting at different levels of endocrine development.     

Chorion gene amplification in Drosophila: A model for metazoan origins of DNA replication and S-phase control.

The mechanisms controlling duplication of the metazoan genome are only beginning to be understood. It is still unclear what organization of DNA sequences constitutes a chromosomal origin of DNA replication, and the regulation of origin activity during the cell cycle has not been fully revealed. We review recent results that indicate that chorion gene amplification in follicle cells of the Drosophila ovary is a model for investigating metazoan replication. Evaluation of cis sequence organization and function suggests that chorion loci share attributes with other replicons and provides insights into metazoan origin structure. Moreover, recent results indicate that chorion origins respond to S-phase control, but escape mechanisms that inhibit other origins from firing more than once in a cell cycle. Several identified genes that mediate amplification are critical for the cell cycle control of replication initiation. It is likely that further genetic screens for mutations that disrupt amplification will identify the cadre of proteins associated with origins and the regulatory pathways that control their activity. Furthermore, the recent development of methods to detect amplification in situ has uncovered new aspects of its developmental control. Examining this control will reveal links between developmental pathways and the cell cycle machinery. Visualization of amplifying chorion genes with high resolution also represents an opportunity to evaluate the influence of nuclear and chromosome structure on origin activity. The study of chorion amplification in Drosophila, therefore, provides great potential for the genetic and molecular dissection of metazoan replication.     

Genetic and developmental basis for parallel evolution and its significance for hominoid evolution

Greater understanding of ape comparative anatomy and evolutionary history has brought a general appreciation that the hominoid radiation is characterized by substantial homoplasy.^1–4 However, little consensus has been reached regarding which features result from repeated evolution. This has important implications for reconstructing ancestral states throughout hominoid evolution, including the nature of the Pan‐Homo last common ancestor (LCA). Advances from evolutionary developmental biology (evo‐devo) have expanded the diversity of model organisms available for uncovering the morphogenetic mechanisms underlying instances of repeated phenotypic change. Of particular relevance to hominoids are data from adaptive radiations of birds, fish, and even flies demonstrating that parallel phenotypic changes often use similar genetic and developmental mechanisms. The frequent reuse of a limited set of genes and pathways underlying phenotypic homoplasy suggests that the conserved nature of the genetic and developmental architecture of animals can influence evolutionary outcomes. Such biases are particularly likely to be shared by closely related taxa that reside in similar ecological niches and face common selective pressures. Consideration of these developmental and ecological factors provides a strong theoretical justification for the substantial homoplasy observed in the evolution of complex characters and the remarkable parallel similarities that can occur in closely related taxa. Thus, as in other branches of the hominoid radiation, repeated phenotypic evolution within African apes is also a distinct possibility. If so, the availability of complete genomes for each of the hominoid genera makes them another model to explore the genetic basis of repeated evolution.     

Beyond Arabidopsis. Translational biology meets evolutionary developmental biology

Developmental processes shape plant morphologies, which constitute important adaptive traits selected for during evolution. Identifying the genes that act in developmental pathways and determining how they are modified during evolution is the focus of the field of evolutionary developmental biology, or evo-devo. Knowledge of genetic pathways in the plant model Arabidopsis serves as the starting point for investigating how the toolkit of developmental pathways has been used and reused to form different plant body plans. One productive approach is to identify genes in other species that are orthologous to genes known to control developmental pathways in Arabidopsis and then determine what changes have occurred in the protein coding sequence or in the gene's expression to produce an altered morphology. A second approach relies on natural variation among wild populations or crop plants. Natural variation can be exploited to identify quantitative trait loci that underlie important developmental traits and, thus, define those genes that are responsible for adaptive changes. The possibility of applying comparative genomics approaches to Arabidopsis and related species promises profound new insights into the interplay of evolution and development.     

Different cell cycle modifications repress apoptosis at different steps independent of developmental signaling in Drosophila

Apoptotic cell death is important for the normal development of a variety of organisms. Apoptosis is also a response to DNA damage and an important barrier to oncogenesis. The apoptotic response to DNA damage is dampened in specific cell types during development. Developmental signaling pathways can repress apoptosis, and reduced cell proliferation also correlates with a lower apoptotic response. However, because developmental signaling regulates both cell proliferation and apoptosis, the relative contribution of cell division to the apoptotic response has been hard to discern in vivo. Here we use Drosophila oogenesis as an in vivo model system to determine the extent to which cell proliferation influences the apoptotic response to DNA damage. We find that different types of cell cycle modifications are sufficient to repress the apoptotic response to ionizing radiation independent of developmental signaling. The step(s) at which the apoptosis pathway was repressed depended on the type of cell cycle modification—either upstream or downstream of expression of the p53-regulated proapoptotic genes. Our findings have important implications for understanding the coordination of cell proliferation with the apoptotic response in development and disease, including cancer and the tissue-specific responses to radiation therapy.     

Developmental constraints vs. variational properties: How pattern formation can help to understand evolution and development

This article suggests that apparent disagreements between the concept of developmental constraints and neo-Darwinian views on morphological evolution can disappear by using a different conceptualization of the interplay between development and selection. A theoretical framework based on current evolutionary and developmental biology and the concepts of variational properties, developmental patterns and developmental mechanisms is presented. In contrast with existing paradigms, the approach in this article is specifically developed to compare developmental mechanisms by the morphological variation they produce and the way in which their functioning can change due to genetic variation. A developmental mechanism is a gene network, which is able to produce patterns in space though the regulation of some cell behaviour (like signalling, mitosis, apoptosis, adhesion, etc.). The variational properties of a developmental mechanism are all the pattern transformations produced under different initial and environmental conditions or IS-mutations. IS-mutations are DNA changes that affect how two genes in a network interact, while T-mutations are mutations that affect the topology of the network itself. This article explains how this new framework allows predictions not only about how pattern formation affects variation, and thus phenotypic evolution, but also about how development evolves by replacement between pattern formation mechanisms. This article presents testable inferences about the evolution of the structure of development and the phenotype under different selective pressures. That is what kind of pattern formation mechanisms, in which relative temporal order, and which kind of phenotypic changes, are expected to be found in development.     

Drosophila sex combs as a model of evolutionary innovations

The diversity of animal and plant forms is shaped by nested evolutionary innovations. Understanding the genetic and molecular changes responsible for these innovations is therefore one of the key goals of evolutionary biology. From the genetic point of view, the origin of novel traits implies the origin of new regulatory pathways to control their development. To understand how these new pathways are assembled in the course of evolution, we need model systems that combine relatively recent innovations with a powerful set of genetic and molecular tools. One such model is provided by the Drosophila sex comb—a male‐specific morphological structure that evolved in a relatively small lineage related to the model species D. melanogaster. Our extensive knowledge of sex comb development in D. melanogaster provides the basis for investigating the genetic changes responsible for sex comb origin and diversification. At the same time, sex combs can change on microevolutionary timescales and differ spectacularly among closely related species, providing opportunities for direct genetic analysis and for integrating developmental and population‐genetic approaches. Sex comb evolution is associated with the origin of novel interactions between Hox and sex determination genes. Activity of the sex determination pathway was brought under the control of the Hox code to become segment‐specific, while Hox gene expression became sexually dimorphic. At the same time, both Hox and sex determination genes were integrated into the intrasegmental spatial patterning network, and acquired new joint downstream targets. Phylogenetic analysis shows that similar sex comb morphologies evolved independently in different lineages. Convergent evolution at the phenotypic level reflects convergent changes in the expression of Hox and sex determination genes, involving both independent gains and losses of regulatory interactions. However, the downstream cell‐differentiation programs have diverged between species, and in some lineages, similar adult morphologies are produced by different morphogenetic mechanisms. These features make the sex comb an excellent model for examining not only the genetic changes responsible for its evolution, but also the cellular processes that translate DNA sequence changes into morphological diversity. The origin and diversification of sex combs provides insights into the roles of modularity, cooption, and regulatory changes in evolutionary innovations, and can serve as a model for understanding the origin of the more drastic novelties that define higher order taxa.     

Elements for a theory of molecular evolution

Biological evolution is known to be driven by the availability of genetic variants. Spontaneous genetic variation can be the result of a number of specific molecular mechanisms. These can be grouped into three qualitatively different natural strategies of generating genetic variations, namely local sequence changes, DNA rearrangement within the genome and horizontal gene transfer, which is referred to here as DNA acquisition. All of these strategies bring about alterations in the DNA sequences of the genome, thus corresponding to the molecular genetic definition of the term mutation. A detailed inspection of specific mechanisms of mutagenesis reveals on the one hand the impact of non-genetic internal and environmental factors, and on the other hand the specific involvement of gene products. The underlying so-called evolution genes can be classified into generators of genetic variations and into modulators of the frequency of genetic variation. These evolution genes are postulated to have themselves undergone biological evolution under the pressure of second-order selection. On the basis of a few selected examples of mutagenesis, elements for a theory of molecular evolution are collected without a claim for completeness. Philosophical dimensions as well as practical aspects of the advanced knowledge on specific molecular mechanisms involved in molecular evolution are also briefly discussed.     

DNA methylation and epigenetic inheritance

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.     

Hereditary stability and variation in evolution and development

Evolution and development are both lineage processes but are often conceptualized as occurring by different and mutually exclusive mechanisms. It is conventionally asserted that evolution occurs via the random generation of diversity and the subsequent survival of those that pass selection. On the other hand, development is too often presented as proceeding via the unfolding of a deterministic program encoded in the DNA sequence. In biology, universal generalizations are rare and dogmas are often wrong for particular cases. Deterministic mechanisms contribute some of the new DNA sequences that subsequently become substrates for natural selection. Conversely, stochastic and selective mechanisms are intrinsic to development, and also to maintenance of the immune, and possibly, nervous systems. Cancer appears to be another process that straddles distinctions between evolutionary and developmental modes of hereditary change and stabilization. DNA sequence changes are an essential feature of many cancers, but there are also aspects of the disease similar to developmental lineage gone awry. The literature suggests that the cellular changes that give rise to cancer occur by mechanisms commonly associated with both evolutionary and developmental lineage pathways.     

Genetic control of size in Drosophila

During the past ten years, significant progress has been made in understanding the basic mechanisms of the development of multicellular organisms. Genetic analysis of the development of Caenorhabditis elegans and Drosophila has unearthed a fruitful number of genes involved in establishing the basic body plan, patterning of limbs, specification of cell fate and regulation of programmed cell death. The genes involved in these developmental processes have been conserved throughout evolution and homologous genes are involved in the patterning of insect and human limbs. Despite these important discoveries, we have learned astonishingly little about one of the most obvious distinctions between animals: their difference in body size. The mass of the smallest mammal, the bumble-bee bat, is 2 g while that of the largest mammal, the blue whale, is 150 t or 150 million grams. Remarkably, even though they are in the same class, body size can vary up to 75-million-fold. Furthermore, this body growth can be finite in the case of most vertebrates or it can occur continuously throughout life, as for trees, molluscs and large crustaceans. Currently, we know comparatively little about the genetic control of body size. In this article we will review recent evidence from vertebrates and particularly from Drosophila that implicates insulin/insulin-like growth factor-I and other growth pathways in the control of cell, organ and body size.     

Maintenance of DNA methylation during the Arabidopsis life cycle is essential for parental imprinting

Imprinted genes are expressed predominantly from either their paternal or their maternal allele. To date, all imprinted genes identified in plants are expressed in the endosperm. In Arabidopsis thaliana, maternal imprinting has been clearly demonstrated for the Polycomb group gene MEDEA (MEA) and for FWA. Direct repeats upstream of FWA are subject to DNA methylation. However, it is still not clear to what extent similar cis-acting elements may be part of a conserved molecular mechanism controlling maternally imprinted genes. In this work, we show that the Polycomb group gene FERTILIZATION-INDEPENDENT SEED2 (FIS2) is imprinted. Maintenance of FIS2 imprinting depends on DNA methylation, whereas loss of DNA methylation does not affect MEA imprinting. DNA methylation targets a small region upstream of FIS2 distinct from the target of DNA methylation associated with FWA. We show that FWA and FIS2 imprinting requires the maintenance of DNA methylation throughout the plant life cycle, including male gametogenesis and endosperm development. Our data thus demonstrate that parental genomic imprinting in plants depends on diverse cis-elements and mechanisms dependent or independent of DNA methylation. We propose that imprinting has evolved under constraints linked to the evolution of plant reproduction and not by the selection of a specific molecular mechanism.     

Genes, pathways and checkpoints in lymphocyte development and homeostasis

A plethora of genes involved in murine B and T cell development have been identified, and developmental pathways within the primary lymphoid tissues have been well delineated. The generation of a functional, but non-self reacting lymphocyte repertoire results from the completion of several checkpoints during lymphocyte development and competition for survival factors in the periphery. Improved knowledge of these developmental checkpoints and homeostatic mechanisms is critical for understanding human immunodeficiency, leukaemia/lymphoma and autoimmunity, which are conditions where checkpoints and homeostasis are likely to be deregulated.     

The Regulation of Dictyostelium Development by Transmembrane Signalling

ABSTRACT. Dictyostelium discoideum has a well characterized life cycle where unicellular growth and multicellular development are separated events. Development is dependent upon signal transduction mediated by cell surface, cAMP receptor/G protein linkages. Secreted cAMP acts extracellularly as a primary signal and chemoattractant. There are 4 genes for the distinct cAMP receptor subtypes, CAR1, CAR2, CAR3 and CAR4. These subtypes are expressed with temporally and spatially specific patterns and cells carrying null mutations for each gene have distinct developmental phenotypes. These results indicate an essential role for cAMP signalling throughout Dictyostelium development to regulate such diverse pathways as cell motility, aggregation (multicellularity), cytodifferentiation, pattern formation and cell type-specific gene expression.