Genes expressed in the ring gland,the major endocrine organ of Drosophila melanogaster.

We have used an enhancer-trap approach to begin characterizing the function of the Drosophila endocrine system during larval development. Five hundred and ten different lethal PZ element insertions were screened to identify those in which a reporter gene within the P element showed strong expression in part or all of the ring gland, the major site of production and release of developmental hormones, and which had a mutant phenotype consistent with an endocrine defect. Nine strong candidate genes were identified in this screen, and eight of these are expressed in the lateral cells of the ring gland that produce ecdysteroid molting hormone (EC). We have confirmed that the genes detected by these enhancer traps are expressed in patterns similar to those detected by the reporter gene. Two of the genes encode proteins, protein kinase A and calmodulin, that have previously been implicated in the signaling pathway leading to EC synthesis and release in other insects. A third gene product, the translational elongation factor EF-1alpha F1, could play a role in the translational regulation of EC production. The screen also identified the genes couch potato and tramtrack, previously known from their roles in peripheral nervous system development, as being expressed in the ring gland. One enhancer trap revealed expression of the gene encoding the C subunit of vacuolar ATPase (V-ATPase) in the medial cells of the ring gland, which produce the juvenile hormone that controls progression through developmental stages. This could reveal a function of V-ATPase in the response of this part of the ring gland to adenotropic neuropeptides. However, the gene identified by this enhancer trap is ubiquitously expressed, suggesting that the enhancer trap is detecting only a subset of its control elements. The results show that the enhancer trap approach can be a productive way of exploring tissue-specific genetic functions in Drosophila.     

The role of epigenetic processes in controlling flowering time in plants exposed to stress

Plants interact with their environment by modifying gene expression patterns. One mechanism for this interaction involves epigenetic modifications that affect a number of aspects of plant growth and development. Thus, the epigenome is highly dynamic in response to environmental cues and developmental changes. Flowering is controlled by a set of genes that are affected by environmental conditions through an alteration in their expression pattern. This ensures the production of flowers even when plants are growing under adverse conditions, and thereby enhances transgenerational seed production. In this review recent findings on the epigenetic changes associated with flowering in Arabidopsis thaliana grown under abiotic stress conditions such as cold, drought, and high salinity are discussed. These epigenetic modifications include DNA methylation, histone modifications, and the production of micro RNAs (miRNAs) that mediate epigenetic modifications. The roles played by the phytohormones abscisic acid (ABA) and auxin in chromatin remodelling are also discussed. It is shown that there is a crucial relationship between the epigenetic modifications associated with floral initiation and development and modifications associated with stress tolerance. This relationship is demonstrated by the common epigenetic pathways through which plants control both flowering and stress tolerance, and can be used to identify new epigenomic players.     

环境雌激素双酚A的研究进展

环境荷尔蒙是现代生命科学领域研究的热点之一,如今越来越多的人开始关注这一话题。在我们的生活环境中充斥着各种化学有毒试剂,其中,有一类物质能够模拟或抑制内分泌激素的活动,我们称之为内分泌干扰物。内分泌干扰物有能力改变内分泌系统的结构和功能。双酚A作为一种环境雌激素,属于内分泌干扰物的一种。双酚A被广泛应用于聚碳酸酯塑料和环氧树脂的制造。双酚A具有弱雌激素效应,能够与雌激素受体结合,引起内分泌系统的应答。目前的研究表明,双酚A会透过血胎屏障影响到胚胎发育,会对神经内分泌系统、肝组织功能以及生殖器的发育造成损伤。本文主要综述了环境雌激素双酚A在小鼠发育阶段所引起的诸多不利影响,并对环境荷尔蒙未来的研究方向进行了展望。     

Stress et Spermatogénèse

Stress, which originates in the brain, can influence spermatogenesis hormonally or via the nervous system. The hormonal route commences with the central secretion of Corticotrophin-Releasing Factor, leading to a fall in LHRH production, a decrease in Leydig cell LH receptors and a decrease in 17 a hydroxylase activity. Thus, in the case of major, prolonged stress, testosterone secretion falls, which in turn affects spermatogenesis. However, given that the testosterone threshold required for normal seminiferous epithelium function is significantly less than the mean circulating level of this hormone, the importance of low intensity stress remains unknown. The nervous route involves catecholaminergic fibres which, in the testis, innervate the Highmore corpus, the vessels, the area adjacent to the Leydig cells, and the basement membrane of seminiferous tubules. The experimental destruction of these fibres leads a regression of the seminiferous epithelium. Moreover, the experimental ablation of the rat anterior neocortex leads to changes in spermatogenesis. Therefore, given that the endocrine system does not seem to be involved in these changes, these results indicate that the highest level of the nervous system may participate in the controlling the germinal epithelium which, all things considered, would tend to support psychosomatic influences. However, given that the number of spermatozoa varies significantly between ejaculate and independantly of the level of testosterone secretion necessary for normal spermatogenesis, it may be hypothesized that it is only when sperm production is low that temporary stress, in aggravating the situation, becomes deleterious to spermatogenesis. Since, under normal conditions, such periods are short, the role of the influence of stress on spermatogenesis can only be relative. Nevertheless, if variations occur during permanently low sperm production, the likelihood of negative effects is increased. Consequently, the impact of stress or psychological factors on spermatogenesis might well depend upon particular circumstances.     

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.     

A role for transcriptional repression during light control of plant development

Light mediates plant development partly by orchestrating changes in gene expression, a process which involves a complex combination of positive and negative signaling cascades. Genetic investigations using the small crucifer Arabidopsis thaliana have demonstrated a fundamental role for the down-regulation of light-inducible genes in response to darkness, thus offering a suitable model system for investigating how plants repress gene expression in a developmental context. Rapid progress in eukaryotic gene repression mechanisms in general, and light control of plant gene expression in particular, sheds new light on how a class of ten pleiotropic COP/DET/FUS genes might function to down-regulate light-inducible genes in plants.     

C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B

Dominantly inherited multiple endocrine neoplasia type 2B (MEN2B) is characterized by tumors of the thyroid C-cells and adrenal chromaffin cells, together with ganglioneuromas of the gastrointestinal tract and other developmental abnormalities. Most cases are caused by substitution of threonine for Met918 in the RET receptor tyrosine kinase, which is believed to convert the RET gene to an oncogene by altering the enzyme's substrate specificity. We report the production of a mouse model of MEN2B by introduction of the corresponding mutation into the ret gene. Mutant mice displayed C-cell hyperplasia and chromaffin cell hyperplasia progressing to pheochromocytoma. Homozygotes did not develop gastrointestinal ganglioneuromas, but displayed ganglioneuromas of the adrenal medulla, enlargement of the associated sympathetic ganglia and a male reproductive defect. Surprisingly, homozygotes did not display any developmental defects attributable to a loss-of-function mutation. Thus, while our results support the conclusion that the Met918Thr substitution is responsible for MEN2B, they suggest that the substrate specificity of the RET kinase does not interfere with its normal role in the development of the kidneys and enteric nervous system.     

The roles of miRNAs in wing imaginal disc development in Drosophila

During development, it is essential for gene expression to occur in a very precise spatial and temporal manner. There are many levels at which regulation of gene expression can occur, and recent evidence demonstrates the importance of mRNA stability in governing the amount of mRNA that can be translated into functional protein. One of the most important discoveries in this field has been miRNAs (microRNAs) and their function in targeting specific mRNAs for repression. The wing imaginal discs of Drosophila are an excellent model system to study the roles of miRNAs during development and illustrate their importance in gene regulation. This review aims at discussing the developmental processes where control of gene expression by miRNAs is required, together with the known mechanisms of this regulation. These developmental processes include Hox gene regulation, developmental timing, growth control, specification of SOPs (sensory organ precursors) and the regulation of signalling pathways.     

Cellular and nerve fibre catecholaminergic thymic network: steroid hormone dependent activity

The thymus plays a critical role in establishing and maintaining the peripheral T-cell pool. It does so by providing a microenvironment within which T-cell precursors differentiate and undergo selection processes to create a functional population of major histocompatibility complex-restricted, self-tolerant T cells. These cells are central to adaptive immunity. Thymic T-cell development is influenced by locally produced soluble factors and cell-to-cell interactions, as well as by sympathetic noradrenergic and endocrine system signalling. Thymic lymphoid and non-lymphoid cells have been shown not only to express beta- and alpha(1)- adrenoceptors (ARs), but also to synthesize catecholamines (CAs). Thus, it is suggested that CAs influence T-cell development via both neurocrine/endocrine and autocrine/paracrine action, and that they serve as immunotransmitters between thymocytes and nerves. CAs acting at multiple sites along the thymocyte developmental route affect T-cell generation not only numerically, but also qualitatively. Thymic CA level and synthesis, as well as AR expression exhibit sex steroid-mediated sexual dimorphism. Moreover, the influence of CAs on T-cell development exhibits glucocorticoid-dependent plasticity. This review summarizes recent findings in this field and our current understanding of complex and multifaceted neuroendocrine-immune communications at thymic level.     

Novel Pancreatic Endocrine Maturation Pathways Identified by Genomic Profiling and Causal Reasoning

We have used a previously unavailable model of pancreatic development, derived in vitro from human embryonic stem cells, to capture a time-course of gene, miRNA and histone modification levels in pancreatic endocrine cells. We investigated whether it is possible to better understand, and hence control, the biological pathways leading to pancreatic endocrine formation by analysing this information and combining it with the available scientific literature to generate models using a casual reasoning approach. We show that the embryonic stem cell differentiation protocol is highly reproducible in producing endocrine precursor cells and generates cells that recapitulate many aspects of human embryonic pancreas development, including maturation into functional endocrine cells when transplanted into recipient animals. The availability of whole genome gene and miRNA expression data from the early stages of human pancreatic development will be of great benefit to those in the fields of developmental biology and diabetes research. Our causal reasoning algorithm suggested the involvement of novel gene networks, such as NEUROG3/E2F1/KDM5B and SOCS3/STAT3/IL-6, in endocrine cell development We experimentally investigated the role of the top-ranked prediction by showing that addition of exogenous IL-6 could affect the expression of the endocrine progenitor genes NEUROG3 and NKX2.2.     

Enchancer detector analysis of the extent of genomic involvement in nervous system development in Drosophila melanogaster

We conducted a survey of the patterns of gene expression in the central nervous system (CNS) of larvae of the fruitfly Drosophila melanogaster to identify genes that may be important in the development of the CNS, aid in the recognition of basic organizing features that might underlie CNS development, and estimate the extent of the use of information encoded in the genome in the construction of the nervous system. A so-called enhancer detector strategy was used to generate many thousands of lines containing a β-galactosidase reporter gene. These lines were screened as third-instar larvae for patterns of expression in the developing optic lobes and other portions of the CNS. Most of the lines recovered which evidence staining within the CNS could be included in one of a relatively small number of patterns. A random sample of 594 lines from the larger population screened was selected to quantify the relative frequencies of these patterns, and a more careful analysis of the changes in the patterns of expression with developmental time was done for representative lines of nine of the patterns. These studies demonstrated great variability in the patterns of gene expression as a function of developmental stage. Few, if any, lines showed β-galactosidase activity limited to the optic lobes; similarly, few lines were identified in which staining was limited to only a small number of cells. Together with the limited number of patterns of gene expression seen, this suggests that in the larval CNS developmental pathways may be controlled by a combinatorial process of gene activity that involves the majority of the genome rather than by having a specific gene specify the fate of only a few neuronal precursors. © 1993 John Wiley & Sons, Inc.     

The role of calcium in hypoxia-induced signal transduction and gene expression

Mammalian cells require a constant supply of oxygen in order to maintain adequate energy production, which is essential for maintaining normal function and for ensuring cell survival. Sustained hypoxia can result in cell death. Sophisticated mechanisms have therefore evolved which allow cells to respond and adapt to hypoxia. Specialized oxygen-sensing cells have the ability to detect changes in oxygen tension and transduce this signal into organ system functions that enhance the delivery of oxygen to tissue in a wide variety of different organisms. An increase in intracellular calcium levels is a primary response of many cell types to hypoxia/ischemia. The response to hypoxia is complex and involves the regulation of multiple signaling pathways and coordinated expression of perhaps hundreds of genes. This review discusses the role of calcium in hypoxia-induced regulation of signal transduction pathways and gene expression. An understanding of the molecular events initiated by changes in intracellular calcium will lead to the development of therapeutic approaches toward the treatment of hypoxic/ischemic diseases and tumors.     

Ecological developmental biology: environmental signals for normal animal development

The environment plays instructive roles in development and selective roles in evolution. This essay reviews several of the instructive roles whereby the organism has evolved to receive cues from the environment in order to modulate its developmental trajectory. The environmental cues can be abiotic (such as temperature or photoperiod) or biotic (such as those emanating from predators, conspecifics, or food), and the “alteration” produces a normal, not a pathological, phenotype, that is appropriate for the environment. In addition, symbiotic organisms can produce important signals during normal development. Environmental cues can be obligatory, such that the organism cannot develop without the environmental cue. These cues often permit and instruct the organism to proceed from one developmental stage to another, as when larvae receive cues to settle and undergo metamorphosis from substrates. Such obligatory cues can also be given by symbionts, as when Wolbachia bacteria prevent apoptosis in developing ovaries of some wasps. Other environmental cues can be used facultatively, allowing organisms to follow different developmental trajectories depending on whether the cue is present or not. This can be seen in the temperature‐dependent determination of sex in many reptiles and in the determination of thermotolerance in aphids by their symbiotic bacteria. Signaling from the environment is essential in development, and co‐development appears to be normative between symbionts and their hosts. Here, one sees the reciprocal induction of gene expression, just as within the embryonic organism. The ability of organisms to respond to environmental cues by producing different phenotypes may be critically important in evolution, and it may be an essential feature that can facilitate or limit evolution.