Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

Developmental mechanisms and experimental models to understand forebrain malformative diseases

The development of the central nervous system can be divided into a number of phases, each of which can be subject of genetic or epigenetic alterations that may originate particular developmental disorders. In recent years, much progress has been made in elucidating the molecular and cellular mechanisms by which the vertebrate forebrain develops. Therefore, our understanding of major developmental brain disorders such as cortical malformations and neuronal migration disorders has significantly increased. In this review, we will describe the major stages in forebrain morphogenesis and regionalization, with special emphasis on developmental molecular mechanisms derailing telencephalic development with subsequent damage to cortical function. Because animal models, mainly mouse, have been fundamental for this progress, we will also describe some characteristic mouse models that have been capital to explore these molecular mechanisms of malformative diseases of the human brain. Although most of the genes involved in the regulation of basic developmental processes are conserved among vertebrates, the extrapolation of mouse data to corresponding gene expression and function in humans needs careful individual analysis in each functional system.     

Liver development and regeneration: from laboratory study to clinical therapy

The liver has an unusual capacity to regenerate after a loss of mass and function caused by surgical resection or toxic liver injury. Over the last 10 years there have been major advances in our understanding of the molecular and cellular mechanisms underlying liver development and regeneration. The numerous factors crucial to these phenomena have been identified mainly by using knockout mice. Forward-genetics studies using zebrafish and medaka have also generated many mutants with liver disorders or defects in liver formation. Our goal is to translate knowledge gained from laboratory work and animal models into novel therapies for human liver diseases. Exciting progress has been achieved using human partial liver transplantation and autologous cell therapy.     

Pathogen virulence factors as molecular probes of basic plant cellular functions

To successfully colonize plants, pathogens have evolved a myriad of virulence factors that allow them to manipulate host cellular pathways in order to gain entry into, multiply and move within, and eventually exit the host for a new infection cycle. In the past few years, substantial progress has been made in characterizing the host targets of viral and bacterial virulence factors, providing unique insights into basic plant cellular processes such as gene silencing, vesicle trafficking, hormone signaling, and innate immunity. Identification of the host targets of additional pathogen virulence factors promises to continue shedding light on fundamental cellular mechanisms in plants, thus enhancing our understanding of plant signaling, metabolism, and cell biology.     

Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?

Plasma measurements of lipids, lipoproteins, and apolipoproteins provide information on the static levels of these fractions without providing key information on the dynamic fluxes of lipoproteins in the circulation. Kinetics studies, in contrast, provide additional information on the production and clearance rates of lipoproteins and the flow of lipids and apolipoproteins through lipoprotein fractions. This information is crucial in accurately delineating the metabolism of HDL in plasma, because plasma concentrations of HDL are the net result of the de novo production and catabolism of HDL as well as the recycling of HDL particles and the contribution to HDL from components of other lipoproteins. Studies aimed at measuring the metabolism of HDL particles have shown that HDL metabolism in vivo is complex and consists of multiple components. Kinetics studies provide a window into the metabolism of HDL, allowing us to better understand the mechanisms of HDL decrease in human conditions and the functionality of HDL particles. Here, we review the progress in our understanding of HDL metabolism derived from in vivo kinetics studies, focusing primarily on studies in humans but also reviewing key studies in animal models.     

The push and pull of the bacterial cytoskeleton

A crucial function for eukaryotic cytoskeletal filaments is to organize the intracellular space: facilitate communication across the cell and enable the active transport of cellular components. It was assumed for many years that the small size of the bacterial cell eliminates the need for a cytoskeleton, because simple diffusion of proteins is rapid over micron-scale distances. However, in the last decade, cytoskeletal proteins have indeed been found to exist in bacteria where they have an important role in organizing the bacterial cell. Here, we review the progress that has been made towards understanding the mechanisms by which bacterial cytoskeletal proteins influence cellular organization. These discoveries have advanced our understanding of bacterial physiology and provided insight into the evolution of the eukaryotic cytoskeleton.     

Cellular bases of behavioral plasticity: establishing and modifying synaptic circuits in the Drosophila genetic system

Genetic malleability and amenability to behavioral assays make Drosophila an attractive model for dissecting the molecular mechanisms of complex behaviors, such as learning and memory. At a cellular level, Drosophila has contributed a wealth of information on the mechanisms regulating membrane excitability and synapse formation, function, and plasticity. Until recently, however, these studies have relied almost exclusively on analyses of the peripheral neuromuscular junction, with a smaller body of work on neurons grown in primary culture. These experimental systems are, by themselves, clearly inadequate for assessing neuronal function at the many levels necessary for an understanding of behavioral regulation. The pressing need is for access to physiologically relevant neuronal circuits as they develop and are modified throughout life. In the past few years, progress has been made in developing experimental approaches to examine functional properties of identified populations of Drosophila central neurons, both in cell culture and in vivo. This review focuses on these exciting developments, which promise to rapidly expand the frontiers of functional cellular neurobiology studies in Drosophila. We discuss here the technical advances that have begun to reveal the excitability and synaptic transmission properties of central neurons in flies, and discuss how these studies promise to substantially increase our understanding of neuronal mechanisms underlying behavioral plasticity.     

Towards mechanistic models of plant organ growth

Modelling and simulation are increasingly used as tools in the study of plant growth and developmental processes. By formulating experimentally obtained knowledge as a system of interacting mathematical equations, it becomes feasible for biologists to gain a mechanistic understanding of the complex behaviour of biological systems. In this review, the modelling tools that are currently available and the progress that has been made to model plant development, based on experimental knowledge, are described. In terms of implementation, it is argued that, for the modelling of plant organ growth, the cellular level should form the cornerstone. It integrates the output of molecular regulatory networks to two processes, cell division and cell expansion, that drive growth and development of the organ. In turn, these cellular processes are controlled at the molecular level by hormone signalling. Therefore, combining a cellular modelling framework with regulatory modules for the regulation of cell division, expansion, and hormone signalling could form the basis of a functional organ growth simulation model. The current state of progress towards this aim is that the regulation of the cell cycle and hormone transport have been modelled extensively and these modules could be integrated. However, much less progress has been made on the modelling of cell expansion, which urgently needs to be addressed. A limitation of the current generation models is that they are largely qualitative. The possibilities to characterize existing and future models more quantitatively will be discussed. Together with experimental methods to measure crucial model parameters, these modelling techniques provide a basis to develop a Systems Biology approach to gain a fundamental insight into the relationship between gene function and whole organ behaviour.     

Transgenic mouse models for the prevention of breast cancer

Breast cancer prevention research has made remarkable progress in the past decade. Much of this progress has come from clinical trials. However, in the future to test the many promising agents that are now available, pre-clinical models of breast cancer are needed. Such models are now available. Useful models include rat and mouse models, particularly, the genetically engineered mice (GEM). Many transgenic mouse models have been generated by manipulating growth factors and their receptors, cell cycle regulators, signal transduction pathways, cellular differentiation, oncogenes and tumor suppressor genes. The transgenes are induced to express in the mouse mammary glands under the control of various transgenic promoters, which have respective characteristics in expression pattern and other biological attributes. These models are providing invaluable insight on the molecular mechanisms of breast tumorigenesis. In this review, we discuss the relative relevance of the most commonly used transgenic mouse models for breast cancer prevention studies, and provide examples of how these transgenic models can be used to conduct cancer prevention research. Due to the multi-factor, multi-step nature of breast cancer, many factors should be incorporated into a valid prevention study. However, many barriers to progress must be overcome, including access to and availability of new cancer preventive drugs, and difficulties in conducting studies of combinations of preventive agents.     

Murine mutants in the study of systemic iron metabolism and its disorders: an update on recent advances

Many past and recent advances in the field of iron metabolism have relied upon the use of mouse models of disease. These models have arisen spontaneously in breeder colonies or have been engineered for global or conditional ablation or overexpression of select genes. Full phenotypic characterization of these models typically involves maintenance on iron-loaded or -deficient diets, treatment with oxidative or hemolytic agents, breeding to other mutant lines or other stresses. In this review, we focus on systemic iron biology and the contributions that mouse model-based studies have made to the field. We have divided the field into three broad areas of research: dietary iron absorption, regulation of hepcidin expression and cellular iron metabolism. For each area, we begin with an overview of the current understanding of key molecular and cellular determinants then discuss recent advances. Finally, we conclude with brief comments on prospects for future study. This article is part of a Special Issue entitled: Cell Biology of Metals.     

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.     

RNA interference: a tool for querying nervous system function and an emerging therapy

RNA interference (RNAi), a mediator of gene silencing, has swiftly become one of the most exciting and applicable biological discoveries. There has been rapid progress in identifying RNAi pathway components and elucidating the mechanisms of microRNA (miRNA) biogenesis and gene suppression. As a result, RNAi technologies have been successfully employed in a variety of systems as biological tools, and studies are underway to test the therapeutic utility of RNAi. In the span of several years, significant advances in the delivery of inhibitory RNAs in the nervous system have been made. We have glimpses into how endogenous miRNAs interface with neuronal development and function; in addition, RNAi has shown therapeutic efficacy in several mouse models of human neurological conditions. In this review, we summarize the current state-of-the-art of RNAi and its utility to neuroscientists.     

Fungal metabolite analysis in genomics and phenomics

Metabolomics consists of strategies to quantitatively identify cellular metabolites and to understand how trafficking of these biochemical messengers through the metabolic network influences phenotype. The application of metabolomics to fungi has been strongly pursued because these organisms are widely used for the production of chemicals, are well known for their diverse metabolic landscape and serve as excellent eukaryotic model organisms for studying metabolism and systems biology. Within the context of fungal systems, recent progress has been made in the development of analytical tools and mathematical strategies used in metabolite analysis that have enhanced our ability to crack the code underpinning the cellular inventory, regulatory schemes and communication mechanisms that dictate cellular function. Metabolomics has played a key role in functional genomics and strain classification.     

Maneuvering for advantage: the genetics of mouse susceptibility to virus infection

Genetic studies of host susceptibility to infection contribute to our understanding of an organism's response to pathogens at the immunological, cellular, and molecular levels. In this review we describe how the study of host genetics in mouse models has helped our understanding of host defense mechanisms against viral infection, and how this knowledge can be extended to human infections. We focus especially on the innate mechanisms that function as the host's first line of defense against infection. We also discuss the main issues that confront this field, as well as its future.     

A mouse model of Werner Syndrome: what can it tell us about aging and cancer?

The molecular mechanisms involved in mammalian aging and the consequent organ dysfunction/degeneration pathologies are not well understood. Studies of progeroid syndromes such as Werner Syndrome have advanced our understanding of how certain genetic pathways can influence the aging process on both cellular and molecular levels. In addition, improper maintenance of telomere length and the consequent cellular responses to dysfunctional telomeres have been proposed to promote replicative senescence that impact upon the onset of premature aging and cancer. Recent studies of the telomerase-Werner double null mouse link telomere dysfunction to accelerated aging and tumorigenesis in the setting of Werner deficiency. This mouse model thus provides a unique genetic platform to explore molecular mechanisms by which telomere dysfunction and loss of WRN gene function leads to the onset of premature aging and cancer.     

DNA转座子在小鼠基因功能研究中的应用

近年来,转座子介导的插入突变在哺乳动物的分子遗传学研究中得到了广泛的应用。转座子作为一种简便高效的遗传学操作工具,在构建转基因动物模型、基因治疗、细胞水平和动物整体水平的基因功能研究等方面发挥了重要的作用。文章重点介绍DNA转座子的结构、功能及其应用于小鼠分子遗传学领域的最新研究进展。