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UC Santa Barbara UC Santa Barbara Previously Published Works Title Integrins in the development, function and dysfunction of the nervous system. Permalink https://escholarship.org/uc/item/90h3m29x Journal Frontiers in bioscience : a journal and virtual library, 8(4) ISSN 1093-9946 Authors Clegg, Dennis O Wingerd, Kevin L Hikita, Sherry T et al. Publication Date 2003-05-01 DOI 10.2741/1020 Peer reviewed eScholarship.org Powered by the California Digital Library University of California [Frontiers in Bioscience 8, d723-750, May 1, 2003] INTEGRINS IN THE DEVELOPMENT, FUNCTION AND DYSFUNCTION OF THE NERVOUS SYSTEM Dennis O. Clegg, Kevin L. Wingerd, Sherry T. Hikita, Erin C. Tolhurst Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California Santa Barbara, California TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Integrins in the Nervous System 3.1. Migration of Neuroblasts 3.2. Axon and Dendrite Outgrowth 3.3. Synapse Formation 3.3.1. Neuromuscular Junction 3.3.2. CNS Synapses 3.4. Synaptic Plasticity and Memory and Learning 3.5. Glial Integrins 3.6. Integrins in Neural Disease 3.6.1.Pathogenic Infection 3.6.2.Demyelinating Disease 3.6.3.Cancer 3.6.4.Injury, Repair and Regeneration 3.6.5.Neurodegenerative Disease 3.6.6. Retinal Disease 4. Conclusion 5. References 1. ABSTRACT Integrin receptors mediate cell-cell and cell- and generate dendrites and axons, often with elaborate extracellular matrix (ECM) interactions in many different branches and patterns. Another unique requirement is to cell types, including neuronal cells. Earlier studies have make specialized synaptic contacts with other cells. shown a clear role for integrins in axon extension and cell Synapses are assembled with as many as 1000 partners, and adhesion/migration in CNS inflammation. Here we they are maintained as plastic structures that can be summarize more recent work that shows integrin functions modified by experience. In light of these requirements, it is in many phases of neural development, from neuroblast no surprise that neurons express an extensive array of cell migration to synapse formation. Integrins of the beta-1 and adhesion molecules (CAMs), including immunoglobulin alpha-v family are widely expressed on neurons at many family receptors, cadherins, and integrins. In this review, stages of development, and their activity is regulated. we will summarize recent studies of the integrin family of Integrins are also important in the adult nervous system, receptors in the nervous system. Since their discovery in since they have been implicated in synaptic plasticity 1986, over 21,000 papers have been published on integrins, involved in memory and learning. In addition, several and over 2000 of these are reviews! However, few of these diseases of the nervous system appear to involve beta-1, focus on the roles fulfilled by integrins in the development beta-2, and alpha-v integrins on leukocytes and glial cells. and function of the nervous system. Research challenges for the future include understanding functions of specific integrin heterodimers and identifying Integrins are a family of (alpha-beta) the relevant integrin ligands that function in the nervous heterodimeric receptors that mediate both cell-cell and cell- system. matrix interactions in a wide variety of cell types (1-3). Recent analyses of whole genomes have provided insights 2. INTRODUCTION into the phylogenetic distribution of integrins (4-6). Proteins distantly related to integrins have been detected in Neuronal cells have unique requirements for their yeast (7), and more convincing integrin homologues have proper development and function. First, they must get to been identified in sponges (8). Thus, integrins in their the right place. This requires a sometimes long migrational current form appear to have arisen coincidentally with a journey by neuroblasts involving contact with many cells metazoan lifestyle. Caenorhabditis elegans has 4 alpha and substrates. Following migration, neurons differentiate subunit genes and 2 beta subunit genes, and Drosophila 723 Integrins in the Nervous System melanogaster has 7 integrin alpha genes and 2 beta genes Upon binding ligand, integrins are known to (5). It is estimated that the fly has 500 or so genes cluster into point contacts that mature to become focal implicated in cell adhesion events (including receptors and contacts or focal adhesions (22). This clustering is an ligands), which accounts for 4% of the genome (4). The important aspect of “outside-in” signal transduction, since sequencing of the human genome uncovered 24 alpha and 9 signaling can be induced by treatment of cells with anti- beta subunit genes, whereas previous studies had identified integrin antibodies. Part of this clustering is brought about 18 alpha and 8 ?beta subunits (5). It will be interesting to see by the proximity of multiple ligands present in polymeric if the integrins predicted can be verified and further matrix networks. The focal adhesion that is assembled is a characterized. specialized multiprotein anchorage complex that links to actin stress fibers. Focal adhesions contain a complex array Table 1 shows the integrin heterodimers that have of interacting proteins, such as talin, alpha-actinin, been identified and characterized to date, with known vinculin, and paxillin. Integrin beta subunit cytoplasmic ligands. Although all combinations of alpha and beta are domains interact with Focal Adhesion Kinase (FAK) and not possible, and only 24 integrin heterodimers have been activate the kinase upon ligand binding (2, 3, 23, 24). Once characterized thus far, the complexity is greater than this integrins bind their ligands, they are thought to assemble a because some alpha and beta subunits have splice variants signaling complex that includes FAK, SRC, GRB2, with different distributions and different signaling p130CAS, SHC, integrin-linked kinase, paxillin, properties (9, 10). For example, the beta-1 subunit has 5 calreticulin, caveolin-1 and other signaling elements that cytoplasmic splice variants, and one can act as a dominant are still being identified. Integrins can activate the MAP negative to another (11). A single integrin heterodimer can kinase pathway and increase intracellular pH and Ca2+. often bind more than one ligand, and a single ECM ligand The complex web of intracellular signaling events initiated is often recognized by multiple integrins. For example, at by integrin receptors is also thought to involve the small least 7 integrins are capable of binding laminin-1, and 9 GTPases rho, rac, and cdc42. These proteins are important integrins have been reported to bind fibronectin (12). regulators of actin polymerization dynamics during Integrins mediate interactions with cell surface ligands such movement of filipodia and lamellipodia (22). Recently as cell adhesion molecules in the Ig superfamily, and evidence has been presented that integrins may signal to ADAMs family disintegrins. Integrins also serve as induce apoptosis in the absence of ligand (25). It has docking sites for viruses and bacteria, and play a role in become clear that the signaling pathways used by integrins sperm binding to eggs (13). The list of integrin ligands are the same ones used by many other factors, and we are continues to grow, and, based on the sequence of the just beginning to understand the complex crosstalk between human genome, reports of novel integrins are likely (14, receptor systems (26). 15). Integrins can associate within the membrane (in At first glance, it appears that there is a great deal of cis) with other transmembrane receptors (27). These overlap in integrin function. However, the apparent receptors are believed to bind ligands and signal via the redundancy has not been reflected in studies of knockout associated integrin. This widens the repertoire of ligands mice lacking integrin genes. Twenty of 22 subunit that use integrins. These include tetraspan receptors such as knockouts show striking phenotypes and 10 are lethal (16- CD-9, which can mediate fertilization, neurite outgrowth 18). These and other studies have implicated integrins in a and myoblast fusion (13, 28, 29), and integrin-associated wide array of cellular processes, including cell adhesion, protein (IAP), a thrombospondin/p84 receptor that may cell spreading, cell migration, cellular polarization, axon play a role in memory and learning (30). outgrowth, synapse formation, myoblast fusion, apoptosis, cell division, phagocytosis, and changes in gene expression. Integrin binding affinity and specificity is Physiological processes thought to require integrin function regulated via “inside–out” signaling mechanisms that are include thrombosis, inflammation, synaptic plasticity, thought to involve small GTPases (such as R-ras) and alter angiogenesis, vasculogenesis, fertilization, tissue repair, associations between alpha and beta subunit cytoplasmic tumor cell metastasis, and a variety of developmental domains (3, 21, 31). Factors that bind to other receptors can events. stimulate integrins via this mechanism. Regulatory conformational changes can also be induced by ligand Both alpha and beta subunits span the membrane binding. In addition, expression is regulated at the once, and most have relatively short cytoplasmic domains transcriptional level. For example, cells can respond to the (except for the beta-4 subunits). Recent x-ray composition of the underlying ECM and modify integrin crystallographic studies of integrin extracellular