WIP is a negative regulator of neuronal maturation and synaptic activity.

Wiskott-Aldrich syndrome protein (WASP) -interacting protein (WIP) is an actin-binding protein involved in the regulation of actin polymerization in cells, such as fibroblasts and lymphocytes. Despite its recognized function in non-neuronal cells, the role of WIP in the central nervous system has not been examined previously. We used WIP-deficient mice to examine WIP function both in vivo and in vitro. We report here that WIP(-)(/-) hippocampal neurons exhibit enlargement of somas as well as overgrowth of neuritic and dendritic branches that are more evident in early developmental stages. Dendritic arborization and synaptogenesis, which includes generation of postsynaptic dendritic spines, are actin-dependent processes that occur in parallel at later stages. WIP deficiency also increases the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting that WIP(-)(/-) neurons have more mature synapses than wild-type neurons. These findings reveal WIP as a previously unreported regulator of neuronal maturation and synaptic activity.

[1]  C. Stevens,et al.  Development regulates a switch between post- and presynaptic strengthening in response to activity deprivation , 2009, Proceedings of the National Academy of Sciences.

[2]  F. Polleux,et al.  Establishment of axon-dendrite polarity in developing neurons. , 2009, Annual review of neuroscience.

[3]  Cecilia Conde,et al.  Microtubule assembly, organization and dynamics in axons and dendrites , 2009, Nature Reviews Neuroscience.

[4]  Alissa M. Weaver,et al.  N-WASP and the Arp2/3 Complex Are Critical Regulators of Actin in the Development of Dendritic Spines and Synapses* , 2008, Journal of Biological Chemistry.

[5]  Malgorzata Urbanska,et al.  Molecular basis of dendritic arborization. , 2008, Acta neurobiologiae experimentalis.

[6]  Susumu Mori,et al.  Filopodia are required for cortical neurite initiation , 2007, Nature Cell Biology.

[7]  R. Geha,et al.  WASP-interacting protein (WIP): working in polymerisation and much more. , 2007, Trends in cell biology.

[8]  M. Kessels,et al.  Regulation of N-WASP and the Arp2/3 Complex by Abp1 Controls Neuronal Morphology , 2007, PloS one.

[9]  W. Lim,et al.  Multiple WASP-interacting Protein Recognition Motifs Are Required for a Functional Interaction with N-WASP* , 2007, Journal of Biological Chemistry.

[10]  R. Geha,et al.  A novel anti-WIP monoclonal antibody detects an isoform of WIP that lacks the WASP binding domain. , 2007, Biochemical and biophysical research communications.

[11]  P. Musiani,et al.  WIP null mice display a progressive immunological disorder that resembles Wiskott–Aldrich syndrome , 2007, The Journal of pathology.

[12]  I. Curtis.  Intracellular Mechanisms For Neuritogenesis , 2007 .

[13]  S. Kaech,et al.  Culturing hippocampal neurons , 2006, Nature Protocols.

[14]  S. Tsuboi,et al.  A Complex of Wiskott-Aldrich Syndrome Protein with Mammalian Verprolins Plays an Important Role in Monocyte Chemotaxis1 , 2006, The Journal of Immunology.

[15]  Wei Zhang,et al.  Pten Regulates Neuronal Arborization and Social Interaction in Mice , 2006, Neuron.

[16]  C. Hoogenraad,et al.  Control of Dendritic Arborization by the Phosphoinositide-3′-Kinase–Akt–Mammalian Target of Rapamycin Pathway , 2005, The Journal of Neuroscience.

[17]  Tony Pawson,et al.  Polarity proteins in axon specification and synaptogenesis. , 2005, Developmental cell.

[18]  Elena B. Pasquale,et al.  Molecular mechanisms of dendritic spine development and remodeling , 2005, Progress in Neurobiology.

[19]  K. Kollins,et al.  Branching Morphogenesis in Vertebrate Neurons , 2005 .

[20]  S. Gygi,et al.  Toca-1 Mediates Cdc42-Dependent Actin Nucleation by Activating the N-WASP-WIP Complex , 2004, Cell.

[21]  M. Kirschner,et al.  Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation , 2004, Nature Structural &Molecular Biology.

[22]  H. Katoh,et al.  Identification of Splicing Variants of Rapostlin, a Novel Rnd2 Effector that Interacts with Neural Wiskott-Aldrich Syndrome Protein and Induces Neurite Branching* , 2004, Journal of Biological Chemistry.

[23]  J. Hartwig,et al.  WIP Regulates Signaling via the High Affinity Receptor for Immunoglobulin E in Mast Cells , 2004, The Journal of experimental medicine.

[24]  W. Witke,et al.  RhoA/ROCK regulation of neuritogenesis via profilin IIa–mediated control of actin stability , 2003, The Journal of cell biology.

[25]  T. Takenawa,et al.  Small GTPase Tc10 and its homologue RhoT induce N-WASP-mediated long process formation and neurite outgrowth , 2003, Journal of Cell Science.

[26]  W. Lim,et al.  Structure of the N-WASP EVH1 Domain-WIP Complex Insight into the Molecular Basis of Wiskott-Aldrich Syndrome , 2002, Cell.

[27]  Shiro Suetsugu,et al.  Sustained activation of N-WASP through phosphorylation is essential for neurite extension. , 2002, Developmental cell.

[28]  Carlos G. Dotti,et al.  Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis , 2002, Nature Reviews Neuroscience.

[29]  H. Katoh,et al.  Rho family GTPases as key regulators for neuronal network formation. , 2002, Journal of biochemistry.

[30]  T. Takenawa,et al.  Spatial and temporal regulation of actin polymerization for cytoskeleton formation through Arp2/3 complex and WASP/WAVE proteins. , 2002, Cell motility and the cytoskeleton.

[31]  J. Hartwig,et al.  WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation. , 2002, Immunity.

[32]  Liqun Luo,et al.  Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. , 2002, Annual review of cell and developmental biology.

[33]  P. Burger,et al.  Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease , 2001, Nature Genetics.

[34]  J. Hartwig,et al.  WIP regulates N-WASP-mediated actin polymerization and filopodium formation , 2001, Nature Cell Biology.

[35]  H. Cline,et al.  Dendritic arbor development and synaptogenesis , 2001, Current Opinion in Neurobiology.

[36]  R. Nicoll,et al.  PSD-95 involvement in maturation of excitatory synapses. , 2000, Science.

[37]  Á. Acebes,et al.  Cellular and molecular features of axon collaterals and dendrites , 2000, Trends in Neurosciences.

[38]  W. Lim,et al.  Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. , 2000, Science.

[39]  A. McAllister,et al.  Cellular and molecular mechanisms of dendrite growth. , 2000, Cerebral Cortex.

[40]  Hollis T. Cline,et al.  Postsynaptic CPG15 promotes synaptic maturation and presynaptic axon arbor elaboration in vivo , 2000, Nature Neuroscience.

[41]  Ann Y. Nakayama,et al.  Small GTPases Rac and Rho in the Maintenance of Dendritic Spines and Branches in Hippocampal Pyramidal Neurons , 2000, The Journal of Neuroscience.

[42]  B. Neel,et al.  A Role for Nuclear PTEN in Neuronal Differentiation , 2000, The Journal of Neuroscience.

[43]  H. Cline,et al.  Dendritic Dynamics In Vivo Change during Neuronal Maturation , 1999, The Journal of Neuroscience.

[44]  C. Dotti,et al.  The role of local actin instability in axon formation. , 1999, Science.

[45]  J. Partridge,et al.  Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses , 1999, Nature Neuroscience.

[46]  Shiro Suetsugu,et al.  WAVE, a novel WASP‐family protein involved in actin reorganization induced by Rac , 1998, The EMBO journal.

[47]  Peter Somogyi,et al.  Cell Type and Pathway Dependence of Synaptic AMPA Receptor Number and Variability in the Hippocampus , 1998, Neuron.

[48]  J. Ávila,et al.  Regulation of a site-specific phosphorylation of the microtubule-associated protein 2 during the development of cultured neurons , 1998, Neuroscience.

[49]  Niraj S. Desai,et al.  Activity-dependent scaling of quantal amplitude in neocortical neurons , 1998, Nature.

[50]  Yoshimi Takai,et al.  Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP , 1998, Nature.

[51]  J. Hartwig,et al.  WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Huganir,et al.  Redistribution and Stabilization of Cell Surface Glutamate Receptors during Synapse Formation , 1997, The Journal of Neuroscience.

[53]  A. Ferreira,et al.  The expression of acetylated microtubules during axonal and dendritic growth in cerebellar macroneurons which develop in vitro. , 1989, Brain research. Developmental brain research.

[54]  D. Kernell,et al.  Dendrites of cat's spinal motoneurones: relationship between stem diameter and predicted input conductance. , 1989, The Journal of physiology.

[55]  G. Banker,et al.  The establishment of polarity by hippocampal neurons in culture , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  P. Rakić,et al.  The mode of migration of neurons to the hippocampus: a Golgi and electron microscopic analysis in foetal rhesus monkey , 1979, Journal of neurocytology.

[57]  Sholl Da.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953 .

[58]  D. Sholl.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953, Journal of anatomy.