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      The Proprotein Convertase KPC-1/Furin Controls Branching and Self-avoidance of Sensory Dendrites in Caenorhabditis elegans

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          Abstract

          Animals sample their environment through sensory neurons with often elaborately branched endings named dendritic arbors. In a genetic screen for genes involved in the development of the highly arborized somatosensory PVD neuron in C. elegans, we have identified mutations in kpc-1, which encodes the homolog of the proprotein convertase furin. We show that kpc- 1/furin is necessary to promote the formation of higher order dendritic branches in PVD and to ensure self-avoidance of sister branches, but is likely not required during maintenance of dendritic arbors. A reporter for kpc-1/furin is expressed in neurons (including PVD) and kpc- 1/furin can function cell-autonomously in PVD neurons to control patterning of dendritic arbors. Moreover, we show that kpc- 1/furin also regulates the development of other neurons in all major neuronal classes in C. elegans, including aspects of branching and extension of neurites as well as cell positioning. Our data suggest that these developmental functions require proteolytic activity of KPC-1/furin. Recently, the skin-derived MNR-1/menorin and the neural cell adhesion molecule SAX-7/L1CAM have been shown to act as a tripartite complex with the leucine rich transmembrane receptor DMA-1 on PVD mechanosensory to orchestrate the patterning of dendritic branches. Genetic analyses show that kpc-1/furin functions in a pathway with MNR-1/menorin, SAX-7/L1CAM and DMA-1 to control dendritic branch formation and extension of PVD neurons. We propose that KPC-1/furin acts in concert with the ‘menorin’ pathway to control branching and growth of somatosensory dendrites in PVD.

          Author Summary

          Sensory neurons receive input from other neurons or sample their environment through elaborate structures termed dendritic trees. The correct patterning of dendritic trees is crucial for the proper function of the nervous system, and ample evidence points to the involvement of dendritic defects in a wide range of neuropsychiatric diseases. However, we still do not understand fully how this process is regulated at the molecular level. We discovered an important role for the protein-processing enzyme KPC-1/furin in the development of touch-sensitive dendritic trees in the roundworm C. elegans. Animals lacking this enzyme show multiple defects in the size, shape and number of these dendritic branches as well as other neurons. We further show that the gene encoding KPC-1 is expressed widely in the nervous system and that it is required within the branching neuron to exert its function on dendritic growth. Finally, we reveal a genetic connection between KPC-1 function and genes of the menorin pathway, which was recently discovered to also play an essential role in dendrite development. Thus, our findings add new insight into the molecular understanding of dendrite formation.

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          Most cited references 33

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          Dendritic anomalies in disorders associated with mental retardation.

          Dendritic abnormalities are the most consistent anatomical correlates of mental retardation (MR). Earliest descriptions included dendritic spine dysgenesis, which was first associated with unclassified MR, but can also be found in genetic syndromes associated with MR. Genetic disorders with well-defined dendritic anomalies involving branches and/or spines include Down, Rett and fragile-X syndromes. Cytoarchitectonic analyses also suggest dendritic pathology in Williams and Rubinstein-Taybi syndromes. Dendritic abnormalities appear to have syndrome-specific pathogenesis and evolution, which correlate to some extent with their cognitive profile. The significance of dendritic pathology in synaptic circuitry and the role of animal models in the study of MR-associated dendritic abnormalities are also discussed. Finally, a model of genotype to neurologic phenotype pathway in MR, centered in dendritic abnormalities, is postulated.
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            The dendritic tree and brain disorders.

            Dendrite morphogenesis is a complex but well-orchestrated process and includes the development of dendritic branches, forming characteristic dendrite arbors, and dendritic spines, allowing neurons to communicate with each other. Various studies report that many neuropsychiatric disorders are characterized by dendritic and synaptic pathology, including abnormal spine density and morphology, synapse loss, and aberrant synaptic signaling and plasticity. In this review, we discuss dendrite development and branching, and in specific, morphology, cytoskeletal architecture, and how the complexity of the dendrite tree and its functional capabilities are altered in various brain disorders. Identifying and understanding these changes in dendrite morphology are essential for understanding brain function in normal and disease states. Copyright © 2012 Elsevier Inc. All rights reserved.
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              The biology and therapeutic targeting of the proprotein convertases.

              The mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. Seven of these (proprotein convertase 1 (PC1), PC2, furin, PC4, PC5, paired basic amino acid cleaving enzyme 4 (PACE4) and PC7) activate cellular and pathogenic precursor proteins by cleavage at single or paired basic residues, whereas subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9) regulate cholesterol and/or lipid homeostasis via cleavage at non-basic residues or through induced degradation of receptors. Proprotein convertases are now considered to be attractive targets for the development of powerful novel therapeutics. In this Review, we summarize the physiological functions and pathological implications of the proprotein convertases, and discuss proposed strategies to control some of their activities, including their therapeutic application and validation in selected disease states.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                September 2014
                18 September 2014
                : 10
                : 9
                Affiliations
                [1 ]Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America
                [2 ]Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, United States of America
                University of California San Diego, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YS NJRS HEB. Performed the experiments: YS NJRS. Analyzed the data: YS NJRS HEB. Contributed to the writing of the manuscript: YS NJRS HEB.

                Article
                PGENETICS-D-14-01067
                10.1371/journal.pgen.1004657
                4169376
                25232734

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                Funding
                This work was funded in part through the NIH (R01HD055380 and R21NS081505 to HEB; P30HD071593 and P30CA013330 to Albert Einstein College of Medicine) and a Human Genome Pilot Project from Albert Einstein College of Medicine. NJRS is the recipient of a Fulbright fellowship. HEB is an Irma T. Hirschl/Monique Weill-Caullier research fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Genetics
                Neuroscience
                Developmental Neuroscience
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Genetics

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