Oxygen-reactive species and antioxidant responses during development: the metabolic paradox of cellular differentiation

Metabolic gradients are established during early phases of development and their existence influences subsequent developmental events. Variations in oxygen supply and oxygen metabolism associated with the gradation of metabolic rate in embryos appear to form one basis for the influence of metabolic gradients on development. The rate of oxygen metabolism affects the rate of oxidant generation by various cellular biochemical pathways. Cells contain antioxidant defenses that respond to variations in cellular oxidant production. Large changes in the activity of the antioxidant enzyme superoxide dismutase and changes in cellular redox state occur during the differentiation of many types of cells. These changes correspond to an increased rate of oxidant production; the cellular environment becomes more prooxidizing during differentiation. Evidence is presented that implicates oxidants as a factor that can stimulate alterations in gene expression. Possible mechanisms by which oxidants influence gene expression are also discussed.     

Integrin signaling in skeletal development and function

Integrins are cell surface receptors that connect extracellular matrix (ECM) components to the actin cytoskeleton and transmit chemical and mechanical signals into the cells through adhesion complexes. Integrin‐activated downstream pathways have been implicated in the regulation of various cellular functions, including proliferation, survival, migration, and differentiation. Integrin‐based attachment to the matrix plays a central role in development, tissue morphogenesis, adult tissue homeostasis, remodeling and repair, and disturbance of the ECM‐integrin‐cytoskeleton signaling axis often results in diseases and tissue dysfunction. Increasing amount of in vitro and in vivo evidences suggest that integrins are pivotal for proper development, function, and regeneration of skeletal tissues. In this paper, we will summarize and discuss the role of integrins in skeletogenesis and their influence on the physiology and pathophysiology of cartilage, bone, and tendon. Birth Defects Research (Part C) 102:13–36, 2014. © 2014 Wiley Periodicals, Inc.     

Tissue and age-specificity of post-translational modifications of N-cadherin during chick embryo development

Our previous studies indicated that regulation of N-cadherin expression differs spatially and temporally among tissues of the eye, possibly reflecting the distinct roles it has in the development and maintenance of eye tissues. To understand this regulation of N-cadherin expression and its function in different tissues during embryonic development, we investigated the post-translational modifications of N-cadherin and its association with the cytoskeleton. We show that N-cadherin is a sulfated and phosphorylated protein. The phosphorylation of N-cadherin occurs in an age- and tissue-specific pattern during development in the neural retina, brain, lens and heart. The extent of sulfation of N-cadherin is also age-dependent, and both sulfated and unsulfated pools of N-cadherin exist in the same tissue as indicated by two-dimensional electrophoresis. The degree of association of N-cadherin with the cytoskeleton differs from one tissue to another, as well as within a single tissue at different stages of development. A positive correlation was found between the extent, developmental timing, and tissue specificity of N-cadherin phosphorylation and the degree of N-cadherin association with the cytoskeleton. Our results suggest the existence of a microheterogeneous population of N-cadherin molecules, within which posttranslational modification of N-cadherin may affect its association with the cytoskeleton and its expression and function during development.     

Molecular biology of cadherins in the nervous system

Cadherins are cell-cell adhesion molecules belonging to the Ca²⁺-dependent cadherin superfamily. In the last few years the number of cadherins identified in the nervous system has increased considerably. Cadherins are integral membrane glycoproteins. They are structurally closely related and interspecies homologies are high. The function is mediated through a homophilic binding mechanism, and intracellular proteins, directly or indirectly connected to the cadherins and the cytoskeleton, are necessary for cadherin activity. Cadherins have been implicated in segregation and aggregation of tissues at early developmental stages and in growth and guidance of axons during nervous system development. These functions are modified by changes in type(s) and amount of cadherins expressed at different developmental stages. The regulatory elements guiding cadherin expression are currently being elucidated.     

An epigenetic perspective on the free radical theory of development

The development of organisms requires concerted changes in gene activity. The free radical theory of development proposes that oxygen serves as a morphogen to educe development by influencing the production of metabolic oxidants such as free radicals and reactive oxygen species. One of the central tenets of this theory is that these metabolic oxidants influence development by altering the antioxidant capacity of cells by changing their production of glutathione (GSH). Here we extend on these principles by linking GSH production and oxygen sensing in the control of gene expression to establish the epigenotype of cells during development. We prescribe this novel role to GSH and oxygen during development because these metabolites influence the activity of enzymes responsible for initiating and perpetuating epigenetic control of gene expression. Increased GSH production influences epigenetic processes including DNA and histone methylation by limiting the availability of S-adenosylmethionine, the cofactor utilized during epigenetic control of gene expression by DNA and histone methyltransferases. Moreover, the recent discovery of histone demethylases that require oxygen as a cofactor directly links epigenetic processes to oxygen gradients during development.     

Molecular and cellular aspects of auxin-transport-mediated development

The plant hormone auxin is frequently observed to be asymmetrically distributed across adjacent cells during crucial stages of growth and development. These auxin gradients depend on polar transport and regulate a wide variety of processes, including embryogenesis, organogenesis, vascular tissue differentiation, root meristem maintenance and tropic growth. Auxin can mediate such a perplexing array of developmental processes by acting as a general trigger for the change in developmental program in cells where it accumulates and by providing vectorial information to the tissues by its polar intercellular flow. In recent years, a wealth of molecular data on the mechanism of auxin transport and its regulation has been generated, providing significant insights into the action of this versatile coordinative signal.     

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.     

Two γ-tubulin isoforms are differentially expressed during development in Helianthus annuus

The cytoskeleton is involved in major developmental events in plant cell growth and differentiation. Nucleation events play a key role in the dynamic and organization of the microtubule (Mt) cytoskeleton. Among many proteins involved in Mt nucleation, γ -tubulin has been identified as an essential component of the Mt organizing centers (MTOC). In protoplasts, somatic embryogenesis induction has been correlated with remodeling of Mt cytoskeleton. We have investigated the specific developmental expression of γ -tubulin in Helianthus annuus . Two γ -tubulin isoforms have been detected by immunoblotting, with bands at 52 and 58 kDa. The larger γ -tubulin (58 kDa) is present in all the sunflower tissues tested and is associated with the nucleus. The smaller γ -tubulin (52 kDa), differing from the former at the carboxy-terminal end, is only present in meristematic and dedifferentiated cells and is not bound to the nucleus. This first demonstration of the presence of two γ -tubulins in plant cells is discussed in terms of distinct roles in the nucleation and organization of Mts.     

Semaphorins in the development,homeostasis and disease of hormone systems

Semaphorin proteins are among the best-studied families of guidance cues. Initially characterized as repulsive neuronal guidance cues, during the last decade, significant progress has been made in defining their involvement in the regulation of dynamic changes in the cellular cytoskeleton during embryonic and postnatal neuronal development, under both physiological and pathological conditions. However, semaphorins are not restricted to the nervous system but widely expressed in other tissues, where they play key roles in angiogenesis and organogenesis.In recent years, there has been an increasing emphasis on the potential influence of semaphorins on the development and homeostasis of hormone systems, and conversely, how circulating reproductive hormones regulate semaphorin expression. In this review, we summarize recent studies analyzing the contribution of semaphorin signaling to the morphogenesis, differentiation and plasticity of fundamental neuroendocrine and endocrine systems that regulate key physiological processes, such as reproduction, bone formation and the control of energy homeostasis.     

Arabidopsis VILLIN2 and VILLIN3 act redundantly in sclerenchyma development via bundling of actin filaments

The organization of the actin cytoskeleton has been implicated in sclerenchyma development. However, the molecular mechanisms linking the actin cytoskeleton to this process remain poorly understood. In particular, there have been no studies showing that direct genetic manipulation of the actin cytoskeleton affects sclerenchyma development. Villins belong to the villin/gelsolin/fragmin superfamily and are versatile actin-modifying proteins. Several recent studies have implicated villins in tip growth of single cells, but how villins act in multicellular plant development remains largely unknown. Here, we found that two closely related villin isovariants from Arabidopsis, VLN2 and VLN3, act redundantly in sclerenchyma development. Detailed analysis of cross-sections from inflorescence stems of vln2 vln3 double mutant plants revealed a reduction in stem size and in the number of vascular bundles; however, no defects in synthesis of the secondary cell wall were detected. Surprisingly, the vln2 vln3 double mutation did not affect cell elongation of inter-fascicular fibers. Biochemical analyses showed that recombinant VLN2 was able to cap, sever and bundle actin filaments, similar to VLN3. Consistent with these biochemical activities, loss of function of VLN2 and VLN3 resulted in a decrease in the amount of F-actin and actin bundles in plant cells. Collectively, our findings demonstrate that VLN2 and VLN3 act redundantly in sclerenchyma development via bundling of actin filaments.     

The mechanism of Drosophila leg development along the proximodistal axis

During development of higher organisms, most patterning events occur in growing tissues. Thus, unraveling the mechanism of how growing tissues are patterned into final morphologies has been an essential subject of developmental biology. Limb or appendage development in both vertebrates and invertebrates has attracted great attention from many researchers for a long time, because they involve almost all developmental processes required for tissue patterning, such as generation of the positional information by morphogen, subdivision of the tissue into distinct parts according to the positional information, localized cell growth and proliferation, and control of adhesivity, movement and shape changes of cells. The Drosophila leg development is a good model system, upon which a substantial amount of knowledge has been accumulated. In this review, the current understanding of the mechanism of Drosophila leg development is described.     

Requirements for Arabidopsis ATARP2 and ATARP3 during epidermal development

Plant cells employ the actin cytoskeleton to stably position organelles, as tracks for long distance transport, and to reorganize the cytoplasm in response to developmental and environmental cues. While diverse classes of actin binding proteins have been implicated in growth control, the mechanisms of cytoskeletal reorganization and the cellular functions of specific actin filament arrays are unclear. Arabidopsis trichome morphogenesis includes distinct requirements for the microtubule and actin filament cytoskeletons. It also is a genetically tractable process that is providing new knowledge about cytoskeleton function in plants. The "distorted group" of mutants defines a class of at least eight genes that are required during the actin-dependent phase of trichome growth. Using map-based cloning and a candidate gene approach, we identified mutations in ARP3 (ATARP3) and ARP2 (ATARP2) genes as the cause of the distorted1 (dis1) and wurm (wrm) phenotypes, respectively. ARP2 and ARP3 are components of the evolutionarily conserved ARP2/3 complex that nucleates actin filament polymerization [3]. Mutations in DIS1 and WRM caused severe trichome growth defects but had relatively mild effects on shoot development. DIS1 rescued the phenotype of Deltaarp3 when overexpressed in S. cerevisiae. Developing dis1 trichomes had defects in cytoplasmic actin bundle organization and reduced relative amounts of cytoplasmic actin filaments in developing branches.     

Chemotactic cell movement during Dictyostelium development and gastrulation

Many developmental processes involve chemotactic cell movement up or down dynamic chemical gradients. Studies of the molecular mechanisms of chemotactic movement of Dictyostelium amoebae up cAMP gradients highlight the importance of PIP3 signaling in the control of cAMP-dependent actin polymerization, which drives the protrusion of lamellipodia and filopodia at the leading edge of the cell, but also emphasize the need for myosin thick filament assembly and motor activation for the contraction of the back of the cell. These process become even more important during the multicellular stages of development, when propagating waves of cAMP coordinate the chemotactic movement of tens of thousands of cells, resulting in multicellular morphogenesis. Recent experiments show that chemotaxis, especially in response to members of the FGF, PDGF and VEGF families of growth factors, plays a key role in the guidance of mesoderm cells during gastrulation in chick, mouse and frog embryos. The molecular mechanisms of signal detection and signaling to the actin-myosin cytoskeleton remain to be elucidated.     

Family life at close quarters: communication and constraint in angiosperm seed development

The formation of viable angiosperm seeds involves the co-ordinated growth and development of three genetically distinct organisms, the maternally derived seed coat and the zygotic embryo and endosperm. The physical relationships of these tissues are initially established during the specification and differentiation of the female gametophyte within the tissues of the developing ovule. The molecular programmes implicated in both ovule and seed development involve elements of globally important pathways (such as auxin signalling), as well as ovule- and seed-specific pathways. Recurrent themes, such as the precisely controlled death of specific cell types and the regulation of cell–cell communication and nutrition by the selective establishment of symplastic and apoplastic barriers, appear to play key roles in both pre- and post-fertilization seed development. Much of post-fertilization seed growth occurs during a key developmental window shortly after fertilization and involves the dramatic expansion of the young endosperm, constrained by surrounding maternal tissues. The complex tissue-specific regulation of carbohydrate metabolism in specific seed compartments has been shown to provide a driving force for this early seed expansion. The embryo, which is arguably the most important component of the seed, appears to be only minimally involved in early seed development. Given the evolutionary and agronomic importance of angiosperm seeds, the complex combination of communication pathways which co-ordinate their growth and development remains remarkably poorly understood.     

Coronin proteins as multifunctional regulators of the cytoskeleton and membrane trafficking

Coronins constitute an evolutionarily conserved family of WD-repeat actin-binding proteins, which can be clearly classified into two distinct groups based on their structural features. All coronins possess a conserved basic N-terminal motif and three to ten WD repeats clustered in one or two core domains. Dictyostelium and mammalian coronins are important regulators of the actin cytoskeleton, while the fly Dpod1 and the yeast coronin proteins crosslink both actin and microtubules. Apart from that, several coronins have been shown to be involved in vesicular transport. C. elegans POD-1 and Drosophila coro regulate the actin cytoskeleton, but also govern vesicular trafficking as indicated by mutant phenotypes. In both organisms, defects in cytoskeleton and trafficking lead to severe developmental defects ranging from abnormal cell division to aberrant formation of morphogen gradients. Finally, mammalian coronin 7 appears not to execute any cytoskeleton-related functions, but rather participates in regulating Golgi trafficking. Here, we review recent data providing more insight into molecular mechanisms underlying the regulation of F-actin structures, cytoskeletal rearrangements and intracellular membrane transport by coronin proteins and the way that they might link cytoskeleton with trafficking in development and disease.     

Rho GTPases and activity-dependent dendrite development

Dendritic morphology has an important influence on neuronal information processing. Multiple environmental cues, including neuronal activity, the neurotrophin family of growth factors, and extracellular guidance molecules have been shown to influence dendritic size, shape, and development. The Rho GTPases have emerged as key integrators of these environmental cues to regulate the underlying dendritic cytoskeleton.     

Close link between development and function of gamma-delta T cells

Murine γδ T cells develop as the first T-cell lineage within the fetal thymus and disproportionately localize in mucosal tissues such as lung, skin, uterus, and intestine of adult mice. These unique developmental features and distribution patterns of γδ T cells enable rapid functioning against various insults from pathogens. γδ T cells are also able to respond to local inflammation and consequently regulate the pathogenesis of autoimmune disorders and development of tumors in mice and humans. Hence, it is clinically important to understand the mechanisms that regulate γδ T cell functions. Recent evidence has shown that generations of effector γδ T cell subsets producing IFN-γ, IL-4, and IL-17 are programmed in the murine thymus before their migration to peripheral tissues. This review outlines our current understanding of the development and function of γδ T cells as they influence both innate and acquired immunity.