Regulation of cell migration during tracheal development in Drosophila melanogaster

Most of the knowledge concerning the intracellular mechanisms involved in cell locomotion have been obtained from in vitro studies of cells in culture. Many of the concepts derived from these studies have been partially confirmed in in vivo systems but numerous questions regarding the developmental control of cell migration remain to be addressed. Tracheal morphogenesis in Drosophila melanogaster embryos represents an in vivo model system to study the genetic control of cell migration. We review what is known about tracheal development and regulation of tracheal cell migration. We try to link these in vivo studies and the movement of cells over two dimensional substrates and elaborate on important questions which remain to be addressed in the future.     

The genetics of cell migration in Drosophila melanogaster and Caenorhabditis elegans development.

Cell migrations are found throughout the animal kingdom and are among the most dramatic and complex of cellular behaviors. Historically, the mechanics of cell migration have been studied primarily in vitro, where cells can be readily viewed and manipulated. However, genetic approaches in relatively simple model organisms are yielding additional insights into the molecular mechanisms underlying cell movements and their regulation during development. This review will focus on these simple model systems where we understand some of the signaling and receptor molecules that stimulate and guide cell movements. The chemotactic guidance factor encoded by the Caenorhabditis elegans unc-6 locus, whose mammalian homolog is Netrin, is perhaps the best known of the cell migration guidance factors. In addition, receptor tyrosine kinases (RTKs), and FGF receptors in particular, have emerged as key mediators of cell migration in vivo, confirming the importance of molecules that were initially identified and studied in cell culture. Somewhat surprisingly, screens for mutations that affect primordial germ cell migration in Drosophila have revealed that enzymes involved in lipid metabolism play a role in guiding cell migration in vivo, possibly by producing and/or degrading lipid chemoattractants or chemorepellents. Cell adhesion molecules, such as integrins, have been extensively characterized with respect to their contribution to cell migration in vitro and genetic evidence now supports a role for these receptors in certain instances in vivo as well. The role for non-muscle myosin in cell motility was controversial, but has now been demonstrated genetically, at least in some cell types. Currently the best characterized link between membrane receptor signaling and regulation of the actin cytoskeleton is that provided by the Rho family of small GTPases. Members of this family are clearly essential for the migrations of some cells; however, key questions remain concerning how chemoattractant and chemorepellent signals are integrated within the cell and transduced to the cytoskeleton to produce directed cell migration. New types of genetic screens promise to fill in some of these gaps in the near future.     

Regulation of cell adhesion and migration in lens development

Cell movements during lens development and differentiation involve dynamic regulation of cell-matrix and cell-cell adhesion. How these processes are regulated depends on the particular array of matrix components and adhesion proteins that are expressed, as well as the signaling pathways that affect them. This review examines what is known about adhesion proteins and their regulation in the lens in light of recent findings about the mechanism of cell migration. The characteristic shape and organization of the lens depends on highly regulated cell movements during development and differentiation. Epithelial cells at the equator migrate posteriorly, bringing them into contact with factors in the vitreous humor and initiating differentiation. Elongation of the differentiating fiber cells is coupled with directed migration, posteriorly along the capsule and anteriorly along the fiber cell-epithelial interface, to generate a symmetrically organized fiber cell mass with aligned suture planes. To make these movements, cells systematically create and dissolve cell-cell and cell-matrix adhesions, form connections between these adhesions and the cytoskeleton, and generate contractile force. Since errors in cell migration may lead to aberrant lens shape or misplacement of the lens sutures, precise regulation of each step is essential for the optical quality of the lens. Recent advances in cellular developmental biology have begun to shed light on the molecular mechanisms underlying cell movements and the changes in adhesion that make them possible. This review will summarize those findings and relate them to relevant studies of the lens to provide an outline of the cellular events that lead to lens morphogenesis.     

A conformation hypothesis for the suppressor and promoter functions of p53 in cell growth control and in cancer.

Cancer is a genetic disease caused by defective control of cell proliferation. As cancer cells divide, the genetic defect is inherited by each daughter cell, leading to tumour development with possible progression to malignancy. The identification of those genes linked with cancer is essential for our understanding of the regulation of cell proliferation and for the therapeutic management of cancer cell growth. Recent studies have revealed that p53 is the most commonly affected gene in human cancer. It is a single copy gene and functions in the regulation of cell proliferation. Mutation of p53 is linked with tumour development, and this may involve abnormal functioning of mutant p53 protein. A mutant allele of p53 is functionally temperature-sensitive and can promote or suppress cell proliferation. The tertiary structure of the mutant protein is also sensitive to temperature and adopts promoter and suppressor forms of p53. A conformation model for the functioning of p53 proposes that wild-type p53 is induced to change from suppressor to promoter form during the cell growth response. This model predicts that any mutation that deregulates the normal control of p53 conformation may lead to cancer.     

Role of vimentin in cell migration

Cell migration plays a crucial role in embryonic development, wound healing, regeneration, inflammation, and immune response, as well as in dissemination of malignant tumors. Vimentin is the marker of migrating cells, but its role in cell migration is still unclear. However, recent studies have revealed novel functions for vimentin related to the migration, such as determination of cellular polarity, regulation of cell contact formation, and arrangement and transport of signal proteins involved in cell motility. The review sums up the latest data on vimentin functions and its involvement in molecular mechanisms underlying cell migration. Early studies demonstrated that vimentin expression during embryonic development is associated with cell migration. However, having obtained vimentin knockout mice without apparent impairments in development and ability to reproduce, doubts have appeared if vimentin is required for cell migration during embryonic development. In the present review, we also discuss involvement of vimentin in migration processes at different stages of development and try to resolve current contradictions concerning the role of vimentin in various events of cell migration.     

表遗传学与肿瘤

表遗传学通过对核小体上D NA和组蛋白的结构修饰以及其后导致的染色质结构改变而对局部或整体的基因表达产生重要的调控作用.肿瘤分子生物学研究表明,表遗传学的紊乱与基因的变异一起参与了包括肿瘤细胞生长和分化、细胞周期的调控、D N A修复与重新表达、原癌基因的激活、肿瘤细胞的转移及肿瘤细胞逃避宿主免疫监视等肿瘤发生发展的整个过程.相对于基因变异而言,可逆的表遗传学调控为肿瘤的治疗提供一个全新的方向,而对其分子机制的研究为抗肿瘤药物的设计也提供了一个全新的靶点,从而对肿瘤的临床治疗具有重要的意义.     

Hormonal Regulation of Tomato Fruit Development: A Molecular Perspective

Fruit development is a complex yet tightly regulated process. The developing fruit undergoes phases of cell division and expansion followed by numerous metabolic changes leading to ripening. Plant hormones are known to affect many aspects of fruit growth and development. In addition to the five classic hormones (auxins, gibberellins, cytokinins, abscisic acid and ethylene) a few other growth regulators that play roles in fruit development are now gaining recognition. Exogenous application of various hormones to different stages of developing fruits and endogenous quantifications have highlighted their importance during fruit development. Information acquired through biochemical, genetic and molecular studies is now beginning to reveal the possible mode of hormonal regulation of fruit development at molecular levels. In the present article, we have reviewed studies revealing hormonal control of fruit development using tomato as a model system with emphasis on molecular genetics.     

Transgenic study of energy homeostasis equation: implications and confounding influences.

Recently novel molecular mediators and regulatory pathways for feeding and body weight regulation have been identified in the brain and the periphery. Mice lacking or overexpressing these mediators or receptors have been produced by molecular genetic techniques, and observations on mutant mice have shed new light on the role of each element in the homeostatic loop of body weight regulation. However, the interpretation of the phenotype is under the potential influence of developmental compensation and other genetic and environmental confounds. Specific alterations of the mediators and the consequences of the altered expression patterns are reviewed here and discussed in the context of their functions as suggested from conventional pharmacological studies. Advanced gene targeting strategies in which genes can be turned on or off at desired tissues and times would undoubtedly lead to a better understanding of the highly integrated and redundant systems for energy homeostasis equation.     

Cell biology of embryonic migration

Cell migration is an evolutionarily conserved mechanism that underlies the development and functioning of uni- and multicellular organisms and takes place in normal and pathogenic processes, including various events of embryogenesis, wound healing, immune response, cancer metastases, and angiogenesis. Despite the differences in the cell types that take part in different migratory events, it is believed that all of these migrations occur by similar molecular mechanisms, whose major components have been functionally conserved in evolution and whose perturbation leads to severe developmental defects. These mechanisms involve intricate cytoskeleton-based molecular machines that can sense the environment, respond to signals, and modulate the entire cell behavior. A big question that has concerned the researchers for decades relates to the coordination of cell migration in situ and its relation to the intracellular aspects of the cell migratory mechanisms. Traditionally, this question has been addressed by researchers that considered the intra- and extracellular mechanisms driving migration in separate sets of studies. As more data accumulate researchers are now able to integrate all of the available information and consider the intracellular mechanisms of cell migration in the context of the developing organisms that contain additional levels of complexity provided by extracellular regulation. This review provides a broad summary of the existing and emerging data in the cell and developmental biology fields regarding cell migration during development.     

The receptor function of galactosyltransferase during cellular interactions

Summary The molecular mechanisms that underly cellular interactions during development are still poorly understood. There is reason to believe that complex glycoconjugates participate in cellular interactions by binding to specific cell surface receptors. One class of carbohydrate binding proteins that could serve as receptors during cellular interactions are the glycosyltransferases. Glycosyltransferases have been detected on a variety of cell surfaces, and evidence suggests that they may participate during cellular interactions by binding their specific carbohydrate substrates on adjacent cells or in extracellular matrix (see Refs. 1–4 for review).This review will focus on the receptor function of galactosyltransferase, in particular, during fertilization, embryonic cell adhesion and migration, limb bud morphogenesis, immune recognition and growth control. In many of these systems, the galactosyltransferase substrate has been characterized as a novel, large molecular weight glycoconjugate composed of repeating N-acetyllactosamine residues. The function of surface galactosyl-transferase during cellular interactions has been examined with genetic and biochemical probes, including the T/t-complex morphogenetic mutants, enzyme inhibitors, enzyme modifiers, and competitive substrates. Collectively, these studies suggest that in the mouse, surface galactosyltransferase is under the genetic control of the T/t-complex, and participates in multiple cellular interactions during development by binding to its specific lactosaminoglycan substrate.     

综述: 长链非编码RNA对动脉粥样硬化等疾病影响的研究新进展

动脉粥样硬化是一种以胆固醇等脂质代谢紊乱为主要特征的病理过程,严重影响人类健康．随着遗传学和生物信息学研究的发展,曾被认为无作用的非编码基因序列逐步受到研究者的关注．长链非编码RNA(lncRNA)通过表观遗传调控、转录调控和转录后调控等途径参与剂量补偿效应、基因组印记、细胞发育分化等重要生物学过程,从而影响人类的生长发育、代谢、衰老及疾病等进程．最新研究发现,lncRNA可参与血管内皮细胞的损伤与修复、血管平滑肌细胞的增殖与迁移、巨噬细胞胆固醇的流出与炎症反应、脂质的沉积与斑块的形成等过程,从而影响动脉粥样硬化及其他心血管疾病的发生与发展．     

Centrosome positioning and primary cilia assembly orchestrate neuronal development

Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.     

Glycosphingolipid metabolism and polycystic kidney disease

Sphingolipids and glycosphingolipids are classes of structurally and functionally important lipids that regulate multiple cellular processes, including membrane organization, proliferation, cell cycle regulation, apoptosis, transport, migration, and inflammatory signalling pathways. Imbalances in sphingolipid levels or subcellular localization result in dysregulated cellular processes and lead to the development and progression of multiple disorders, including polycystic kidney disease. This review will describe metabolic pathways of glycosphingolipids with a focus on the evidence linking glycosphingolipid mediated regulation of cell signalling, lipid microdomains, cilia, and polycystic kidney disease. We will discuss molecular mechanisms of glycosphingolipid dysregulation and their impact on cystogenesis. We will further highlight how modulation of sphingolipid metabolism can be translated into new approaches for the treatment of polycystic kidney disease and describe current clinical studies with glucosylceramide synthase inhibitors in Autosomal Dominant Polycystic Kidney Disease.     

Tapetum: regulation and role in sporopollenin biosynthesis in Arabidopsis

Pollen acts as a biological protector for protecting male sperm from various harsh conditions and is covered by an outer cell wall polymer called the exine, a major constituent of which is sporopollenin. The tapetum is in direct contact with the developing gametophytes and plays an essential role in pollen wall and pollen coat formation. The precise molecular mechanisms underlying tapetal development remain highly elusive, but molecular genetic studies have identified a number of genes that control the formation, differentiation, and programmed cell death of tapetum and interactions of genes in tapetal development. Herein, several lines of evidence suggest that sporopollenin is built up via catalytic enzyme reactions in the tapetum. Furthermore, as based on genetic evidence, we review the currently accepted understanding of the molecular regulation of sporopollenin biosynthesis and examine unanswered questions regarding the requirements underpinning proper exine pattern formation.     

Cellular and molecular control of dendritic growth and development of cerebellar Purkinje cells

Purkinje cells are the principal neurons of the cerebellar cortex and are characterized by a large and highly branched dendritic tree. For this reason, they have for a long time been an attractive model system to study the regulation of dendritic growth and differentiation. In this article, I will first review studies on different aspects of Purkinje cell dendritic development and then go on to present studies which have aimed at experimentally altering Purkinje cell dendritic development. Some of the cellular and molecular mechanisms which have been shown by these studies to be important determinants of Purkinje cell dendritic development will be discussed, in particular the role of the parallel fiber input, of hormones, and of neuronal growth factors. The organotypic slice culture method will be introduced as an important experimental tool to study Purkinje cell dendritic development under controlled conditions. Using cerebellar slice cultures, protein kinase C (PKC) has been identified as a major determinant of Purkinje cell dendritic development and the contribution of specific isoforms of PKC will be discussed. Finally, it will be shown that Purkinje cell dendritic development in slice cultures does not depend on the activation of glutamate receptors and appears to be independent of the presence of the neurotrophin BDNF. These studies indicate that the initial outgrowth of the Purkinje cell dendritic tree can occur in the absence of signals derived from afferent fibers, but is under control of PKC signaling.     

Distinct rac activation pathways control Caenorhabditis elegans cell migration and axon outgrowth

Rac GTPases act as molecular switch in various morphogenic events. However, the regulation of their activities during the development of multicellular organisms is not well understood. Caenorhabditis elegans rac genes ced-10 and mig-2 have been shown to act redundantly to control P cell migration and the axon outgrowth of D type motoneurons. We showed that ced-10 and mig-2 also control amphid axon outgrowth and amphid dendrite fasciculation in a redundant fashion. Our biochemical and genetic data indicate that unc-73, which encodes a protein related to Trio-like guanine nucleotide exchange factor, acts as a direct activator of ced-10 and mig-2 during P cell migration and axon outgrowth of D type motoneurons and amphid sensory neurons. Furthermore, rac regulators ced-2/crkII and ced-5/dock180 function genetically upstream of ced-10 and mig-2 during axon outgrowth of D type motoneurons and act upstream of mig-2 but not ced-10 during P cell migration. However, neither ced-2/crkII nor ced-5/dock180 is involved in amphid axon outgrowth. Therefore, distinct rac regulators control ced-10 and mig-2 differentially in various cellular processes.     

性腺母细胞瘤的分子遗传机制研究进展

性腺母细胞瘤(Gonadoblastoma, GB)是一种由性索和生殖细胞演化而来的罕见原位性腺肿瘤,与性腺遗传物质异常有密切联系。80%的GB患者表现为46,XY女性表型,其余为45,XY 和46,XX性别发育异常患者等。35%的GB会进一步演化为无性细胞瘤和精原细胞瘤等恶性肿瘤。由于表型与遗传的异质性,GB的分子遗传机制还未完全揭示。越来越多的研究显示GB的发生与性别分化和决定调控基因(如SRY、WT1、SOX9、Foxl2和TSPY等)之间存在密切关联,且表现出遗传与表观遗传调控相互作用。本文综述了GB的临床表现、病理特征、诊断与治疗措施,总结了性腺遗传异常导致GB的分子遗传与表观遗传调控机制,分析并归纳参与GB形成相关基因的共同表达调控网络,指出了当前研究中的障碍与不足,为进一步研究GB致病分子机制提供新思路。