Showing papers in "Annual Review of Cell and Developmental Biology in 2011"

The Role of Atg Proteins in Autophagosome Formation

Abstract: Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Abstract: Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why in...

The Ins and Outs of the Epithelial to Mesenchymal Transition in Health and Disease

Abstract: The epithelial to mesenchymal transition (EMT) converts epithelial cells into migratory and invasive cells and is a fundamental event in morphogenesis. Although its relevance in the progression of cancer and organ fibrosis had been debated until recently, the EMT is now established as an important step in the metastatic cascade of epithelial tumors. The similarities between pathological and developmental EMTs validate the embryo as the best model to understand the molecular and cellular mechanisms involved in this process, identifying those that are hijacked during the progression of cancer and organ degeneration. Our ever-increasing understanding of how transcription factors regulate the EMT has revealed complex regulatory loops coupled to posttranscriptional and epigenetic regulatory programs. The EMT is now integrated into the systemic activities of whole organisms, establishing links with cell survival, stemness, inflammation, and immunity. In addition, the EMT now constitutes a promising target for the treatment of cancer and organ-degenerative diseases.

Developmental and Pathological Angiogenesis

Abstract: The formation of the vascular network is an intricate and complex process that is an obligate requirement during vertebrate development. The cardiovascular system is the first organ to develop and reach a functional state, which underscores the crucial role of the vasculature in the developing embryo. The development of the vasculature into highly branched conduits needs to occur in numerous sites and in precise patterns to supply oxygen and nutrients to the rapidly expanding tissue of the embryo. This process is mediated by the coordinated response of vascular endothelial and mural cells to the heterogeneous angiogenic cues provided by tissues and organs, whereas aberrant regulation and coordination of angiogenic signals during development result in lethality, impaired organ development, or disease states. This article reviews the essential signaling pathways required for establishment of the vertebrate vasculature with a major focus on a key regulatory factor, vascular endothelial growth factor (VEGF). ...

Gli Proteins in Development and Disease

Abstract: Gli zinc-finger proteins are transcription factors involved in the intracellular signal transduction controlled by the Hedgehog family of secreted molecules. They are frequently mutated in human congenital malformations, and their abnormal regulation leads to tumorigenesis. Genetic studies in several model systems indicate that their activity is tightly regulated by Hedgehog signaling through various posttranslational modifications, including phosphorylation, ubiquitin-mediated degradation, and proteolytic processing, as well as through nucleocytoplasmic shuttling. In vertebrate cells, primary cilia are required for the sensing of Hedgehog pathway activity and involved in the processing and activation of Gli proteins. Two evolutionarily conserved Hedgehog pathway components, Suppressor of fused and Kif7, are core intracellular regulators of mammalian Gli proteins. Recent studies revealed that Gli proteins are also regulated transcriptionally and posttranslationally through noncanonical mechanisms independent of Hedgehog signaling. In this review, we describe the regulation of Gli proteins during development and discuss possible mechanisms for their abnormal activation during tumorigenesis.

Morphogen Gradients: From Generation to Interpretation

Abstract: Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state...

Force Generation, Transmission, and Integration during Cell and Tissue Morphogenesis

Abstract: Cell shape changes underlie a large set of biological processes ranging from cell division to cell motility. Stereotyped patterns of cell shape changes also determine tissue remodeling events such as extension or invagination. In vitro and cell culture systems have been essential to understanding the fundamental physical principles of subcellular mechanics. These are now complemented by studies in developing organisms that emphasize how cell and tissue morphogenesis emerge from the interplay between force-generating machines, such as actomyosin networks, and adhesive clusters that transmit tensile forces at the cell cortex and stabilize cell-cell and cell-substrate interfaces. Both force production and transmission are self-organizing phenomena whose adaptive features are essential during tissue morphogenesis. A new era is opening that emphasizes the similarities of and allows comparisons between distant dynamic biological phenomena because they rely on core machineries that control universal features of cytomechanics.

The Role of MeCP2 in the Brain

Abstract: Methyl-CpG binding protein 2 (MeCP2) was first identified in 1992 as a protein that binds specifically to methylated DNA. Mutations in the MECP2 gene were later found to be the cause of an autism spectrum disorder, Rett syndrome. Despite almost 20 years of research into the molecular mechanisms of MeCP2 function, many questions are yet to be answered conclusively. This review considers several key questions and attempts to evaluate the current state of evidence. For example, is MeCP2 just a methyl-CpG binding protein? Is it a multifunctional protein or primarily a transcriptional repressor? We also consider whether MeCP2, as a chromosome-binding protein, acts at specific sites within the genome or more globally, and in which cell types it is functionally important. Finally, we consider two alternative views of MeCP2 in the brain: as a regulator of brain development or as a factor that helps maintain neuronal/glial function.

Regulation of Integrin Activation

Abstract: Regulation of cell-cell and cell-matrix interaction is essential for the normal physiology of metazoans and is important in many diseases Integrin adhesion receptors can rapidly increase their affinity (integrin activation) in response to intracellular signaling events in a process termed inside-out signaling The transmembrane domains of integrins and their interactions with the membrane are important in inside-out signaling Moreover, integrin activation is tightly regulated by a complex network of signaling pathways Here, we review recent progress in understanding how the membrane environment can, in cooperation with integrin-binding proteins, regulate integrin activation

The Causes and Consequences of Polyploidy in Normal Development and Cancer

Abstract: Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.

Epithelial Progenitor Cells in Lung Development, Maintenance, Repair, and Disease

Abstract: The vertebrate lung is elegantly patterned to carry out gas exchange and host defense. Similar to other organ systems, endogenous stem and progenitor cells fuel the organogenesis of the lung and maintain homeostasis in the face of normal wear and tear. In the context of acute injury, these progenitor populations are capable of effecting efficient repair. However, chronic injury, inflammation, and immune rejection frequently result in pathological airway remodeling and serious impairment of lung function. Here, we review the development, maintenance, and repair of the vertebrate respiratory system with an emphasis on the roles of epithelial stem and progenitor cells. We discuss what is currently known about their identities, lineage relationships, and the mechanisms that regulate their differentiation along various lineages. A deeper understanding of these progenitor populations will undoubtedly accelerate the discovery of improved cellular, genetic, molecular, and bioengineered therapies for lung disease.

Degrading devices: invadosomes in proteolytic cell invasion.

Abstract: Podosomes and invadopodia, collectively known as invadosomes, are cell-matrix contacts in a variety of cell types, such as monocytic cells or cancer cells, that have to cross tissue barriers. Both structures share an actin-rich core, which distinguishes them from other matrix contacts, and are regulated by a multitude of signaling pathways including RhoGTPases, kinases, actin-associated proteins, and microtubule-dependent transport. Invadosomes recruit and secrete proteinases and are thus able to lyse extracellular matrix components. They are therefore considered to be potential key structures in proteolytic cell invasion in both physiological and pathological settings. This review provides an overview of the field, with special focus on current developments such as intracellular transport processes, ultrastructural analysis, the possible involvement of invadosomes in disease, and the tentative identification of invadosomes in 3D environments and in vivo.

Cyclin-dependent kinases in brain development and disease

Abstract: Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegen...

Transmembrane collagen receptors.

Abstract: Collagen, the most abundant protein in animals, is a key component of extracellular matrices. Not only do collagens provide essential structural support for connective tissues, but they are also intimately involved in controlling a spectrum of cellular functions such as growth, differentiation, and morphogenesis. All collagens possess triple-helical regions through which they interact with a host of other proteins including cell surface receptors. A structurally diverse group of transmembrane receptors mediates the recognition of the collagen triple helix: integrins, discoidin domain receptors, glycoprotein VI, and leukocyte-associated immunoglobulin-like receptor-1. These collagen receptors regulate a wide range of behaviors including cell adhesion and migration, hemostasis, and immune function. Here these collagen receptors are discussed in terms of their molecular basis of collagen recognition, their signaling and developmental functions, and their roles in disease.

Mechanisms of T Cell Development and Transformation

Abstract: T cells are the key mediators in cell-mediated immunity. Their development and maturation involve a complex variety of interactions with nonlymphoid cell products and receptors. Highly specialized to defend against bacterial and viral infections, T cells also mediate immune surveillance against tumor cells and react to foreign tissues. T cell progenitors originate in the bone marrow and, through a series of defined and coordinated developmental stages, enter the thymus, differentiate, undergo selection, and eventually mature into functional T cells. The steps in this process are regulated through a complex transcriptional network, specific receptor-ligand pair interactions, and sensitization to trophic factors, which mediate the homing, proliferation, survival, and differentiation of developing T cells. This review examines the processes and pathways involved in the highly orchestrated development of T cell fate specification under physiological as well as pathological conditions.

Dynamin: Functional Design of a Membrane Fission Catalyst

Abstract: Dynamin, best studied for its role in clathrin-mediated endocytosis, is the prototypical member of a family of multidomain GTPases involved in fission and remodeling of multiple organelles. Recent studies have shown that dynamin alone can catalyze fission of membrane tubules and vesicle formation from planar lipid templates. Thus, dynamin appears to be a self-sufficient fission machine. Here we review the biochemical activities and structural features of dynamin required for fission activity. As all changes in membrane topology require energetically unfavorable rearrangements of the lipid bilayer, we discuss the interplay between dynamin and its lipid substrates that are critical to defining a nonleaky pathway to membrane fission. We propose a two-stage model for dynamin-catalyzed fission. In stage one, dynamin's mechanochemical activities induce localized curvature stress and position its lipid-interacting pleckstrin homology domains to create a catalytic center that, in stage two, guides lipid remodeling through hemifission intermediates to drive membrane fission.

Wound repair: toward understanding and integration of single-cell and multicellular wound responses.

Abstract: The importance of wound healing to medicine and biology has long been evident, and consequently, wound healing has been the subject of intense investigation for many years. However, several relatively recent developments have added new impetus to wound repair research: the increasing application of model systems; the growing recognition that single cells have a robust, complex, and medically relevant wound healing response; and the emerging recognition that different modes of wound repair bear an uncanny resemblance to other basic biological processes such as morphogenesis and cytokinesis. In this review, each of these developments is described, and their significance for wound healing research is considered. In addition, overlapping mechanisms of single-cell and multicellular wound healing are highlighted, and it is argued that they are more similar than is often recognized. Based on this and other information, a simple model to explain the evolutionary relationships of cytokinesis, single-cell wound repair, multicellular wound repair, and developmental morphogenesis is proposed. Finally, a series of important, but as yet unanswered, questions is posed.

Membrane protein insertion at the endoplasmic reticulum.

Abstract: Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to overcome these obstacles.

Cooperation Between Integrins and Growth Factor Receptors in Signaling and Endocytosis

Abstract: All multicellular animals express receptors for growth factors (GFs) and extracellular matrix (ECM) molecules. Integrin-type ECM receptors anchor cells to their surroundings and concomitantly activate intracellular signal transduction pathways. The same signaling mechanisms are regulated by GF receptors (GFRs). Recently, intensive research efforts have revealed novel mechanisms describing how the two receptor systems collaborate at many different levels. Integrins can directly bind to GFs and promote their activation. Adhesion receptors also organize signaling platforms and assist GFRs or even activate them via ligand-independent mechanisms. Furthermore, integrins can orchestrate endocytosis and recycling of GFRs. Here, we review the present knowledge about the interplay between integrins and GFRs and discuss recent ideas of how this collaboration may explain some previous controversies in integrin research.

Regulation of Terminal Differentiation Programs in the Nervous System

Abstract: The generation of individual neuron types in the nervous system is a multistep process whose endpoint is the expression of neuron type-specific batteries of terminal differentiation genes that determine the functional properties of a neuron. This review focuses on the regulatory mechanisms that are involved in controlling the terminally differentiated state of a neuron. I review several case studies from invertebrate and vertebrate nervous systems that reveal that many terminal differentiation features of a neuron are coregulated via terminal selector transcription factors that initiate and maintain terminal differentiation programs.

Neurogenesis at the brain-cerebrospinal fluid interface.

Abstract: Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis On one hand, cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle The apical protein complexes themselves are concentrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cerebrospinal fluid We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis

Optogenetic Control of Cells and Circuits

Abstract: The absorption of light by bound or diffusible chromophores causes conformational rearrangements in natural and artificial photoreceptor proteins. These rearrangements are coupled to the opening or closing of ion transport pathways, the association or dissociation of binding partners, the enhancement or suppression of catalytic activity, or the transcription or repression of genetic information. Illumination of cells, tissues, or organisms engineered genetically to express photoreceptor proteins can thus be used to perturb biochemical and electrical signaling with exquisite cellular and molecular specificity. First demonstrated in 2002, this principle of optogenetic control has had a profound impact on neuroscience, where it provides a direct and stringent means of probing the organization of neural circuits and of identifying the neural substrates of behavior. The impact of optogenetic control is also beginning to be felt in other areas of cell and organismal biology.

Limb Regeneration: A New Development?

Abstract: Salamander limb regeneration is a classical model of tissue morphogenesis and patterning. Through recent advances in cell labeling and molecular analysis, a more precise, mechanistic understanding of this process has started to emerge. Long-standing questions include to what extent limb regeneration recapitulates the events observed in mammalian limb development and to what extent are adult- or salamander- specific aspects deployed. Historically, researchers studying limb development and limb regeneration have proposed different models of pattern formation. Here we discuss recent data on limb regeneration and limb development to argue that although patterning mechanisms are likely to be similar, cell plasticity and signaling from nerves play regeneration-specific roles.

Role of leucine-rich repeat proteins in the development and function of neural circuits.

Abstract: The nervous system consists of an ensemble of billions of neurons interconnected in a highly specific pattern that allows proper propagation and integration of neural activities. The organization of these specific connections emerges from sequential developmental events including axon guidance, target selection, and synapse formation. These events critically rely on cell-cell recognition and communication mediated by cell-surface ligands and receptors. Recent studies have uncovered central roles for leucine-rich repeat (LRR) domain-containing proteins, not only in organizing neural connectivity from axon guidance to target selection to synapse formation, but also in various nervous system disorders. Their versatile LRR domains, in particular, serve as key sites for interactions with a wide diversity of binding partners. Here, we focus on a few exquisite examples of secreted or membrane-associated LRR proteins in Drosophila and mammals and review the mechanisms by which they regulate diverse aspects of ner...

Principles of Unconventional Myosin Function and Targeting

Abstract: Unconventional myosins are a superfamily of actin-based motors implicated in diverse cellular processes. In recent years, much progress has been made in describing their biophysical properties, and headway has been made into analyzing their cellular functions. Here, we focus on the principles that guide in vivo motor function and targeting to specific cellular locations. Rather than describe each motor comprehensively, we outline the major themes that emerge from research across the superfamily and use specific examples to illustrate each. In presenting the data in this format, we seek to identify open questions in each field as well as to point out commonalities between them. To advance our understanding of myosins' roles in vivo, clearly we must identify their cellular cargoes and the protein complexes that regulate motor attachment to fully appreciate their functions on the cellular and developmental levels.

Membrane-Anchored Serine Proteases in Vertebrate Cell and Developmental Biology*

Abstract: Analysis of vertebrate genome sequences at the turn of the millennium revealed that a vastly larger repertoire of enzymes execute proteolytic cleavage reactions within the pericellular and extracellular environments than was anticipated from biochemical and molecular analysis. Most unexpected was the unveiling of an entire new family of structurally unique multidomain serine proteases that are anchored directly to the plasma membrane. Unlike secreted serine proteases, which function primarily in tissue repair, immunity, and nutrient uptake, these membrane-anchored serine proteases regulate fundamental cellular and developmental processes, including tissue morphogenesis, epithelial barrier function, ion and water transport, cellular iron export, and fertilization. Here the cellular and developmental biology of this fascinating new group of proteases is reviewed. Particularly highlighted is how the study of membrane-anchored serine proteases has expanded our knowledge of the range of physiological processes that require regulated proteolysis at the cell surface.

Control of Organelle Size: The Golgi Complex

Abstract: The Golgi complex processes secretory proteins and lipids, carries out protein sorting and signaling, and supports growth and composition of the plasma membrane. Golgi complex size likely is regulated to meet the demands of each function, and this may involve differential changes of its distinct subdomains. Nevertheless, the primary size change is elongation of the Golgi ribbon-like network as occurs during Golgi complex doubling for mitosis and during differentiation involving upregulated secretion. One hypothesis states that Golgi complex size is set by the abundance of secretory cargo and Golgi complex components that, through binding vesicle coat complexes, drive vesicle coat formation to alter Golgi complex influx and efflux. Regulation of transport factors controlling Golgi membrane traffic is also observed and may control Golgi complex size, but more work is needed to directly link these events to Golgi complex size regulation, especially during differentiation of specialized cell types.

Sensory Perception and Aging in Model Systems: From the Outside In

Abstract: Sensory systems provide organisms from bacteria to humans with the ability to interact with the world. Numerous senses have evolved that allow animals to detect and decode cues from sources in both their external and internal environments. Recent advances in understanding the central mechanisms by which the brains of simple organisms evaluate different cues and initiate behavioral decisions, coupled with observations that sensory manipulations are capable of altering organismal lifespan, have opened the door for powerful new research into aging. Although direct links between sensory perception and aging have been established only recently, here we discuss these initial discoveries and evaluate the potential for different forms of sensory processing to modulate lifespan across taxa. Harnessing the neurobiology of simple model systems to study the biological impact of sensory experiences will yield insights into the broad influence of sensory perception in mammals and may help uncover new mechanisms of healthy aging.

The Coupling of X-Chromosome Inactivation to Pluripotency

Abstract: X-chromosome inactivation, or the silencing of one X chromosome that occurs initially in the female somatic four-cell-stage embryo, is reversed during embryonic development first at the time of inner cell mass formation and again during formation of germ cell precursors. Such X-chromosome reactivation in the mouse implies the silencing of the Xist gene and the transcription of its antisense partner, Tsix, from both X chromosomes. In murine embryonic stem cells, both genes are under the transcriptional control of a series of critical pluripotency factors, namely, OCT3/4, NANOG, SOX2, KLF4, C-MYC and REX1. Although the inactive/active status of the two X chromosomes present in female human embryonic stem cells remains controversial, the reactivation of X-chromosome inactivation seems to be a signature for the naive pluripotent state.