Polarity proteins in axon specification and synaptogenesis.

The neuron is a prime example of a highly polarized cell. It is becoming clear that conserved protein complexes, which have been shown to regulate polarity in such diverse systems as the C. elegans zygote and mammalian epithelia, are also required for neuronal polarization. This review considers the role of these polarity proteins in axon specification and synaptogenesis.

[1]  V. Budnik,et al.  The drosophila tumor suppressor gene dlg is required for normal synaptic bouton structure , 1994, Neuron.

[2]  Hye Kyong Kweon,et al.  Phosphorylation-Dependent Binding of 14-3-3 to the Polarity Protein Par3 Regulates Cell Polarity in Mammalian Epithelia , 2003, Current Biology.

[3]  P. Aspenström,et al.  The mammalian homologue of the Caenorhabditis elegans polarity protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and Rac1. , 2000, Journal of cell science.

[4]  E. Drier,et al.  New Synaptic Bouton Formation Is Disrupted by Misregulation of Microtubule Stability in aPKC Mutants , 2004, Neuron.

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

[6]  Y. Jan,et al.  APC and GSK-3β Are Involved in mPar3 Targeting to the Nascent Axon and Establishment of Neuronal Polarity , 2004, Current Biology.

[7]  M. White,et al.  Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. , 1998, Science.

[8]  K. Kemphues,et al.  An Atypical PKC Directly Associates and Colocalizes at the Epithelial Tight Junction with ASIP, a Mammalian Homologue of Caenorhabditis elegans Polarity Protein PAR-3 , 1998, The Journal of cell biology.

[9]  Anthony A Hyman,et al.  Asymmetric cell division in C. elegans: cortical polarity and spindle positioning. , 2004, Annual review of cell and developmental biology.

[10]  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.

[11]  R. Kooy Of mice and the fragile X syndrome. , 2003, Trends in genetics : TIG.

[12]  S. Ceman,et al.  Phosphorylation influences the translation state of FMRP-associated polyribosomes. , 2003, Human molecular genetics.

[13]  Y. Jan,et al.  Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. , 1994, Genes & development.

[14]  B. Doble,et al.  Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword? , 2004, Biochemical Society transactions.

[15]  Kendal Broadie,et al.  Fathoming fragile X in fruit flies. , 2005, Trends in genetics : TIG.

[16]  S. Tapscott,et al.  Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. , 2004, Genes & development.

[17]  Anuradha Rao,et al.  Signaling between the actin cytoskeleton and the postsynaptic density of dendritic spines , 2000, Hippocampus.

[18]  Y. Bellaiche,et al.  Mammalian Scribble Forms a Tight Complex with the βPIX Exchange Factor , 2004, Current Biology.

[19]  J. Tavaré,et al.  The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31‐8220) are potent inhibitors of glycogen synthase kinase‐3 activity , 1999, FEBS letters.

[20]  K. Kaibuchi,et al.  CRMP-2 binds to tubulin heterodimers to promote microtubule assembly , 2002, Nature Cell Biology.

[21]  T. Akiyama,et al.  Binding of APC to the Human Homolog of the Drosophila Discs Large Tumor Suppressor Protein , 1996, Science.

[22]  Jérôme Boudeau,et al.  LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 , 2004, The EMBO journal.

[23]  Gerald M. Rubin,et al.  Drosophila Fragile X-Related Gene Regulates the MAP1B Homolog Futsch to Control Synaptic Structure and Function , 2001, Cell.

[24]  A. Suzuki,et al.  aPKC Acts Upstream of PAR-1b in Both the Establishment and Maintenance of Mammalian Epithelial Polarity , 2004, Current Biology.

[25]  M. Nonet,et al.  Cellular and molecular insights into presynaptic assembly , 2001, Current Opinion in Neurobiology.

[26]  Todd Charlton Sacktor,et al.  Memory enhancement and formation by atypical PKM activity in Drosophila melanogaster , 2002, Nature Neuroscience.

[27]  I. Macara,et al.  Par-3 controls tight junction assembly through the Rac exchange factor Tiam1 , 2005, Nature Cell Biology.

[28]  A. Suzuki,et al.  Mammalian Lgl Forms a Protein Complex with PAR-6 and aPKC Independently of PAR-3 to Regulate Epithelial Cell Polarity , 2003, Current Biology.

[29]  M. Monden,et al.  Direct Binding of Cell Polarity Protein PAR-3 to Cell-Cell Adhesion Molecule Nectin at Neuroepithelial Cells of Developing Mouse* , 2003, The Journal of Biological Chemistry.

[30]  C. Dotti,et al.  RhoA, Rac1, and cdc42 intracellular distribution shift during hippocampal neuron development , 2004, Molecular and Cellular Neuroscience.

[31]  E. Mandelkow,et al.  Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. , 2002, Molecular biology of the cell.

[32]  Y. Jan,et al.  Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity , 2003, Cell.

[33]  K. Kemphues,et al.  par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed , 1995, Cell.

[34]  T. Akiyama,et al.  Subcellular localization of the tumor suppressor protein APC in developing cultured neurons , 2005, Neuroscience Letters.

[35]  M. Hatten,et al.  Par6α signaling controls glial-guided neuronal migration , 2004, Nature Neuroscience.

[36]  M. Setou,et al.  Axonal transport versus dendritic transport. , 2004, Journal of neurobiology.

[37]  A. Newton,et al.  Regulation of protein kinase C ζ by PI 3-kinase and PDK-1 , 1998, Current Biology.

[38]  T. Hurd,et al.  Direct interaction of two polarity complexes implicated in epithelial tight junction assembly , 2003, Nature Cell Biology.

[39]  A. Giangrande,et al.  CYFIP/Sra-1 Controls Neuronal Connectivity in Drosophila and Links the Rac1 GTPase Pathway to the Fragile X Protein , 2003, Neuron.

[40]  B. Eickholt,et al.  An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling , 2002, The Journal of cell biology.

[41]  K. Kosik,et al.  Evidence for the Involvement of Tiam1 in Axon Formation , 2001, The Journal of Neuroscience.

[42]  G. Johnson,et al.  Tau phosphorylation: physiological and pathological consequences. , 2005, Biochimica et biophysica acta.

[43]  A. Hyman,et al.  Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation , 2001, Current Biology.

[44]  T. Pawson,et al.  A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl , 2003, Nature Cell Biology.

[45]  P. Pelicci,et al.  Numb Is an Endocytic Protein , 2000, The Journal of cell biology.

[46]  K. Martin Local protein synthesis during axon guidance and synaptic plasticity , 2004, Current Opinion in Neurobiology.

[47]  G. Davis,et al.  Drosophila Futsch/22C10 Is a MAP1B-like Protein Required for Dendritic and Axonal Development , 2000, Neuron.

[48]  M. Sheng,et al.  PDZ domain proteins of synapses , 2004, Nature Reviews Neuroscience.

[49]  S. Antonarakis,et al.  Peutz–Jeghers LKB1 mutants fail to activate GSK-3β, preventing it from inhibiting Wnt signaling , 2005, Molecular Genetics and Genomics.

[50]  J. Mandell,et al.  A Spatial Gradient of Tau Protein Phosphorylation in Nascent Axons , 1996, The Journal of Neuroscience.

[51]  N. Perrimon,et al.  Integrated activity of PDZ protein complexes regulates epithelial polarity , 2003, Nature Cell Biology.

[52]  G. Davis,et al.  Drosophila Futsch Regulates Synaptic Microtubule Organization and Is Necessary for Synaptic Growth , 2000, Neuron.

[53]  K. Mechtler,et al.  The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl , 2003, Nature.

[54]  C. Garner,et al.  The presynaptic cytomatrix of brain synapses , 2001, Cellular and Molecular Life Sciences CMLS.

[55]  M. Bienz APC: the plot thickens. , 1999, Current opinion in genetics & development.

[56]  S. Dedhar,et al.  NGF-Induced Axon Growth Is Mediated by Localized Inactivation of GSK-3β and Functions of the Microtubule Plus End Binding Protein APC , 2004, Neuron.

[57]  Yves Grau,et al.  Shaggy, the Homolog of Glycogen Synthase Kinase 3, Controls Neuromuscular Junction Growth in Drosophila , 2004, The Journal of Neuroscience.

[58]  J. Sanes,et al.  Mammalian SAD Kinases Are Required for Neuronal Polarization , 2005, Science.

[59]  N. Ziv,et al.  Cellular and molecular mechanisms of presynaptic assembly , 2004, Nature Reviews Neuroscience.

[60]  I. Macara,et al.  Structure of Cdc42 in a complex with the GTPase‐binding domain of the cell polarity protein, Par6 , 2003, The EMBO journal.

[61]  T. Hurd,et al.  Pars and polarity: taking control of Rac , 2005, Nature Cell Biology.

[62]  Philip R. Cohen,et al.  Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. , 1998, Science.

[63]  A. Püschel,et al.  The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity , 2004, Nature Neuroscience.

[64]  C. Garner,et al.  The GIT Family of Proteins Forms Multimers and Associates with the Presynaptic Cytomatrix Protein Piccolo* , 2003, The Journal of Biological Chemistry.

[65]  J. Mandell,et al.  Microtubule-associated proteins, phosphorylation gradients, and the establishment of neuronal polarity. , 1996, Perspectives on developmental neurobiology.

[66]  H. Piwnica-Worms,et al.  Atypical PKC Phosphorylates PAR-1 Kinases to Regulate Localization and Activity , 2004, Current Biology.

[67]  Y. Kurachi,et al.  SAP family proteins. , 2000, Biochemical and biophysical research communications.

[68]  Kwang-Wook Choi,et al.  Interaction of Par-6 and Crumbs complexes is essential for photoreceptor morphogenesis in Drosophila , 2003, Development.

[69]  Marc W. Kirschner,et al.  A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity , 2002, Nature Cell Biology.

[70]  R. Benton,et al.  A Conserved Oligomerization Domain in Drosophila Bazooka/PAR-3 Is Important for Apical Localization and Epithelial Polarity , 2003, Current Biology.

[71]  E. Ziff Enlightening the Postsynaptic Density , 1997, Neuron.

[72]  K. Kaibuchi,et al.  CRMP-2 induces axons in cultured hippocampal neurons , 2001, Nature Neuroscience.

[73]  P. Marsh,et al.  Glycogen synthase kinase-3β phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons , 2005, Journal of Cell Science.

[74]  K. Kaibuchi,et al.  CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth , 2003, Nature Cell Biology.

[75]  D. Morton,et al.  The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. , 2000, Development.

[76]  M. Fortini PAR-1 for the Course of Neurodegeneration , 2004, Cell.

[77]  K. Kemphues,et al.  PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos. , 1999, Development.

[78]  A. Abo,et al.  A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCζ signaling and cell transformation , 2000, Current Biology.

[79]  E. Nishida,et al.  The polarity‐inducing kinase Par‐1 controls Xenopus gastrulation in cooperation with 14‐3‐3 and aPKC , 2004, The EMBO journal.

[80]  D. C. Edwards,et al.  Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics , 1999, Nature Cell Biology.

[81]  Y. Takai,et al.  The roles of cadherins and nectins in interneuronal synapse formation , 2003, Current Opinion in Neurobiology.

[82]  Adriana B Ferreira,et al.  LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. , 2004, Molecular biology of the cell.

[83]  A. Hall,et al.  Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity , 2003, Nature.

[84]  I. Macara Par Proteins: Partners in Polarization , 2004, Current Biology.

[85]  K. Kemphues,et al.  Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos , 1995, Cell.

[86]  Paul Herzmark,et al.  Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils , 2002, Nature Cell Biology.

[87]  B. Oostra,et al.  Understanding the biological underpinnings of fragile X syndrome , 2003, Current opinion in pediatrics.

[88]  R. DePinho,et al.  LKB1 (XEEK1) regulates Wnt signalling in vertebrate development , 2003, Nature Cell Biology.

[89]  D. Morton,et al.  The Caenorhabditis elegans par-5 gene encodes a 14-3-3 protein required for cellular asymmetry in the early embryo. , 2002, Developmental biology.

[90]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors , 2000 .

[91]  K. Kaibuchi,et al.  Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity , 2004, Nature Cell Biology.

[92]  Bo Guan,et al.  Regulation of Synapse Structure and Function by the Drosophila Tumor Suppressor Gene dlg , 1996, Neuron.

[93]  Yi Rao,et al.  Axon formation: fate versus growth , 2005, Nature Neuroscience.

[94]  M. Ehlers,et al.  Neuronal Polarity and Trafficking , 2003, Neuron.

[95]  T. Hurd,et al.  Tight Junction Protein Par6 Interacts with an Evolutionarily Conserved Region in the Amino Terminus of PALS1/Stardust* , 2004, Journal of Biological Chemistry.

[96]  K. Kaibuchi,et al.  GSK-3β Regulates Phosphorylation of CRMP-2 and Neuronal Polarity , 2005, Cell.

[97]  Cori Bargmann,et al.  The SAD-1 Kinase Regulates Presynaptic Vesicle Clustering and Axon Termination , 2001, Neuron.

[98]  M. Peifer,et al.  Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila , 2004, The Journal of cell biology.

[99]  T. Hurd,et al.  Polarity Proteins Control Ciliogenesis via Kinesin Motor Interactions , 2004, Current Biology.

[100]  K. Kaibuchi,et al.  Axon specification in hippocampal neurons , 2002, Neuroscience Research.

[101]  Y. Nagai,et al.  PAR‐6 regulates aPKC activity in a novel way and mediates cell‐cell contact‐induced formation of the epithelial junctional complex , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[102]  B. Lu,et al.  PAR-1 Kinase Plays an Initiator Role in a Temporally Ordered Phosphorylation Process that Confers Tau Toxicity in Drosophila , 2004, Cell.

[103]  C. Doe,et al.  Par-6 and aPKC are not required for axon or dendrite specification in Drosophila , 2004 .

[104]  K. Kaibuchi,et al.  PIP3 is involved in neuronal polarization and axon formation , 2004, Journal of neurochemistry.

[105]  R. Goold,et al.  Glycogen synthase kinase 3 β phosphorylation of microtubule-associated protein 1 B regulates the stability of microtubules in growth cones , 1999 .

[106]  D. Bilder Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. , 2004, Genes & development.

[107]  Yuh Nung Jan,et al.  Asymmetric cell division , 1998, Nature.

[108]  Norbert Perrimon,et al.  Recruitment of Scribble to the Synaptic Scaffolding Complex Requires GUK-holder, a Novel DLG Binding Protein , 2002, Current Biology.

[109]  Haigen Huang,et al.  Stimulation of erythropoiesis by inhibiting a new hematopoietic death receptor in transgenic zebrafish , 2000, Nature Cell Biology.

[110]  J. Olefsky,et al.  Insulin-Induced GLUT4 Translocation Involves Protein Kinase C-λ-Mediated Functional Coupling between Rab4 and the Motor Protein Kinesin , 2003, Molecular and Cellular Biology.

[111]  T. Pawson,et al.  A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity , 2000, Nature Cell Biology.

[112]  J. Priess,et al.  Cortical flows powered by asymmetrical contraction transport PAR proteins to establish and maintain anterior-posterior polarity in the early C. elegans embryo. , 2004, Developmental cell.

[113]  R. Jope,et al.  The glamour and gloom of glycogen synthase kinase-3. , 2004, Trends in biochemical sciences.

[114]  U. Tepass,et al.  Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization , 2003, Nature Cell Biology.

[115]  A. Ashworth,et al.  Regulation of the Wnt signalling component PAR1A by the Peutz–Jeghers syndrome kinase LKB1 , 2003, Oncogene.

[116]  E. Van Obberghen,et al.  Insulin Receptor Substrate-2 Phosphorylation Is Necessary for Protein Kinase Cζ Activation by Insulin in L6hIR Cells* , 2001, The Journal of Biological Chemistry.

[117]  Y. Rao,et al.  Both the Establishment and the Maintenance of Neuronal Polarity Require Active Mechanisms Critical Roles of GSK-3β and Its Upstream Regulators , 2005, Cell.

[118]  C. Dotti,et al.  Asymmetric membrane ganglioside sialidase activity specifies axonal fate , 2005, Nature Neuroscience.

[119]  Marion Müller-Borg,et al.  Direct association of Bazooka/PAR-3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling , 2005, Development.

[120]  H. Ropers,et al.  Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation , 2000, Nature Genetics.

[121]  E. Mandelkow,et al.  MARKK, a Ste20‐like kinase, activates the polarity‐inducing kinase MARK/PAR‐1 , 2003, The EMBO journal.

[122]  Mariann Bienz,et al.  The subcellular destinations of apc proteins , 2002, Nature Reviews Molecular Cell Biology.

[123]  L. Van Aelst,et al.  The role of the Rho GTPases in neuronal development. , 2005, Genes & development.

[124]  K. Kemphues,et al.  par-2, a gene required for blastomere asymmetry in Caenorhabditis elegans, encodes zinc-finger and ATP-binding motifs. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[125]  Daniela C. Zarnescu,et al.  Fragile X protein functions with lgl and the par complex in flies and mice. , 2005, Developmental cell.

[126]  Ger J. A. Ramakers,et al.  Rho proteins, mental retardation and the cellular basis of cognition , 2002, Trends in Neurosciences.

[127]  Yuh Nung Jan,et al.  PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling , 2001, Nature Cell Biology.

[128]  Amy S. Gladfelter,et al.  Scaffold-mediated symmetry breaking by Cdc42p , 2003, Nature Cell Biology.

[129]  A. Irving,et al.  GSK-3 Phosphorylation of the Alzheimer Epitope within Collapsin Response Mediator Proteins Regulates Axon Elongation in Primary Neurons* , 2004, Journal of Biological Chemistry.

[130]  Philip Cohen,et al.  GSK3 takes centre stage more than 20 years after its discovery. , 2001 .

[131]  C. Garner,et al.  MAGUKs in synapse assembly and function: an emerging view , 2004, Cellular and Molecular Life Sciences CMLS.

[132]  D. Webb,et al.  Synapse formation is regulated by the signaling adaptor GIT1 , 2003, The Journal of cell biology.

[133]  G. Joberty,et al.  The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42 , 2000, Nature Cell Biology.

[134]  M. Hoshino,et al.  PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1 , 2005, Nature Cell Biology.

[135]  V. Budnik,et al.  Regulation of Synaptic Plasticity and Synaptic Vesicle Dynamics by the PDZ Protein Scribble , 2002, The Journal of Neuroscience.

[136]  A. Harwood,et al.  Cdc42 &GSK-3: signals at the crossroads , 2003, Nature Cell Biology.