The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
Raghu Kalluri, Robert A. Weinberg
Epithelial-mesenchymal transition (EMT) is critical for appropriate embryonic development, and this process is re-engaged in adults during wound healing, tissue regeneration, organ fibrosis, and cancer progression. Inflammation is a crucial conspirator in the emergence of EMT in adults but is absent during embryonic development. As highlighted in this Review series, EMT is now a recognized mechanism for dispersing cells in embryos, forming fibroblasts/mesenchymal cells in injured tissues, and initiating metastasis of epithelial cancer cells. Also discussed are proposals to classify EMT into three subtypes, each of which has different functional consequences.
Raghu Kalluri
The events that convert adherent epithelial cells into individual migratory cells that can invade the extracellular matrix are known collectively as epithelial-mesenchymal transition (EMT). Throughout evolution, the capacity of cells to switch between these two cellular states has been fundamental in the generation of complex body patterns. Here, we review the EMT events that build the embryo and further discuss two prototypical processes governed by EMT in amniotes: gastrulation and neural crest formation. Cells undergo EMT to migrate and colonize distant territories. Not surprisingly, this is also the mechanism used by cancer cells to disperse throughout the body.
Hervé Acloque, Meghan S. Adams, Katherine Fishwick, Marianne Bronner-Fraser, M. Angela Nieto
Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon — namely, the transition of epithelial and endothelial cells to a motile phenotype.
Michael Zeisberg, Eric G. Neilson
Childhood-onset obsessive-compulsive disorder (OCD) affects 1%–2% of children and adolescents. It is characterized by recurrent obsessions and compulsions that create distress and interfere with daily life. The symptoms reported by children are similar to those seen among individuals who develop OCD in adulthood, and the two groups of patients are treated with similar symptom-relieving behavior therapies and medications. However, there are differences in sex ratios, patterns of comorbidity, and the results of neuroimaging studies that might be important. Here we review the diagnosis and treatment of childhood-onset OCD in light of pediatric and adult studies. We also discuss current knowledge of the pathophysiology of the disorder. Despite advances in this area, further research is needed to understand better the etiopathogenesis of the disorder and to develop new, more effective therapeutic options.
Simran K. Kalra, Susan E. Swedo
Schizophrenia is a severe disorder that disrupts the function of multiple brain systems, resulting in impaired social and occupational functioning. The etiology and pathogenesis of schizophrenia appear to involve the interplay of a potentially large number of genetic liabilities and adverse environmental events that disrupt brain developmental pathways. In this Review, we discuss a strategy for determining how particular common and core clinical features of the illness are associated with pathophysiology in certain circuits of the cerebral cortex. The identification of molecular alterations in these circuits is providing critical insights for the rational development of new therapeutic interventions.
David A. Lewis, Robert A. Sweet
Bipolar disorder (BPD) is a devastating illness that is characterized by recurrent episodes of mania and depression. In addition to these cyclic episodes, individuals with BPD exhibit changes in psychovegetative function, cognitive performance, and general health and well being. In this article we draw from neuroimaging findings in humans, postmortem data, and human genetic and pharmacological studies as well as data from animal models of behavior to discuss the neurobiology of BPD. We conclude with a synthesis of where the field stands and with suggestions and strategies for future areas of study to further increase our conceptual understanding of this complex illness.
Keri Martinowich, Robert J. Schloesser, Husseini K. Manji
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.
Pat Levitt, Daniel B. Campbell
During the last 20 years of neuroscience research, we have witnessed a fundamental shift in the conceptualization of psychiatric disorders, with the dominant psychological and neurochemical theories of the past now complemented by a growing emphasis on developmental, genetic, molecular, and brain circuit models. Facilitating this evolving paradigm shift has been the growing contribution of functional neuroimaging, which provides a versatile platform to characterize brain circuit dysfunction underlying specific syndromes as well as changes associated with their successful treatment. Discussed here are converging imaging findings that established a rationale for testing a targeted neuromodulation strategy, deep brain stimulation, for treatment-resistant major depression.
Helen S. Mayberg
Studies over the past 50 years revealing the molecular events that promote normal T lymphocyte cycle competence and progression led to a detailed understanding of how cytokines function to regulate normal hematopoietic cell proliferation. During that same period, the molecular and genetic changes introduced by the Philadelphia chromosome in chronic myelogenous leukemia were unraveled, and these have led to an understanding of how mutations that constitutively activate normal cytokine signaling pathways can cause unregulated cell proliferation and malignant transformation. Based on the paradigm established by these data, it is inescapable that going forward, investigators will operate under the hypothesis that transformation of additional cells and tissues will have a similar pathogenesis.
Kendall A. Smith, James D. Griffin
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