Centrosome positioning and primary cilia assembly orchestrate neuronal development

Abstract

Establishment of axon and dendrite polarity, migration to a desired location in the developing brain, and establishment of proper synaptic connections are essential processes during neuronal development. The cellular and molecular mechanisms that govern these processes are under intensive investigation. The function of the centrosome in neuronal development has been examined and discussed in few recent studies that underscore the fundamental role of the centrosome in brain development. Clusters of emerging studies have shown that centrosome positioning tightly regulates neuronal development, leading to the segregation of cell factors, directed neurite differentiation, neuronal migration, and synaptic integration. Furthermore, cilia, that arise from the axoneme, a modified centriole, are emerging as new regulatory modules in neuronal development in conjunction with the centrosome. In this review, we focus on summarizing and discussing recent studies on centrosome positioning during neuronal development and also highlight recent findings on the role of cilia in brain development. We further discuss shared molecular signaling pathways that might regulate both centrosome and cilia associated signaling in neuronal development. Furthermore, molecular determinants such as DISC1 and LKB1 have been recently demonstrated to be crucial regulators of various aspects of neuronal development. Strikingly, these determinants might exert their function, at least in part, via the regulation of centrosome and cilia associated signaling and serve as a link between these two signaling centers. We thus include an overview of these molecular determinants.

Keywords

centrosome positioning / neuronal polarization/migration / primary cilia

References

[1] Angers S, Moon R T (2009). Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol, 10(7): 468–477

[2] Ansley S J, Badano J L, Blacque O E, Hill J, Hoskins B E, Leitch C C, Kim J C, Ross A J, Eichers E R, Teslovich T M, Mah A K, Johnsen R C, Cavender J C, Lewis R A, Leroux M R, Beales P L, Katsanis N (2003). Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature, 425(6958): 628–633

[3] Arellano J I, Guadiana S M, Breunig J J, Rakic P, Sarkisian M R (2012). Development and distribution of neuronal cilia in mouse neocortex. J Comp Neurol, 520(4): 848–873

[4] Arimura N, Kaibuchi K (2007). Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci, 8(3): 194–205

[5] Asada N, Sanada K (2010). LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex. J Neurosci, 30(26): 8852–8865

[6] Asada N, Sanada K (2007). LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning. The Journal of neuroscience, 27(43): 11769–11775

[7] Baas A F, Boudeau J, Sapkota G P, Smit L, Medema R, Morrice N A, Alessi D R, Clevers H C (2003). Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J, 22(12): 3062–3072

[8] Baas P W, Yu W Q (1996). A composite model for establishing the microtubule arrays of the neuron. Mol Neurobiol, 12(2): 145–161

[9] Badano J L, Katsanis N (2006). Life without centrioles: cilia in the spotlight. Cell, 125(7): 1228–1230

[10] Bai J, Ramos R L, Ackman J B, Thomas A M, Lee R V, LoTurco J J (2003). RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat Neurosci, 6(12): 1277–1283

[11] Baker K, Northam G B, Chong W K, Banks T, Beales P, Baldeweg T (2011). Neocortical and hippocampal volume loss in a human ciliopathy: A quantitative MRI study in Bardet-Biedl syndrome. Am J Med Genet A, 155A(1): 1–8

[12] Barnes A P, Lilley B N, Pan Y A, Plummer L J, Powell A W, Raines A N, Sanes J R, Polleux F (2007). LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell, 129(3): 549–563

[13] Barnes A P, Polleux F (2009). Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci, 32(1): 347–381

[14] Basto R, Lau J, Vinogradova T, Gardiol A, Woods C G, Khodjakov A, Raff J W (2006). Flies without centrioles. Cell, 125(7): 1375–1386

[15] Bielas S, Higginbotham H, Koizumi H, Tanaka T, Gleeson J G (2004). Cortical neuronal migration mutants suggest separate but intersecting pathways. Annu Rev Cell Dev Biol, 20(1): 593–618

[16] Bielas S L, Serneo F F, Chechlacz M, Deerinck T J, Perkins G A, Allen P B, Ellisman M H, Gleeson J G (2007). Spinophilin facilitates dephosphorylation of doublecortin by PP1 to mediate microtubule bundling at the axonal wrist. Cell, 129(3): 579–591

[17] Biernat J, Gustke N, Drewes G, Mandelkow E M, Mandelkow E (1993). Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron, 11(1): 153–163

[18] Bishop G A, Berbari N F, Lewis J, Mykytyn K (2007). Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol, 505(5): 562–571

[19] Blacque O E, Reardon M J, Li C, McCarthy J, Mahjoub M R, Ansley S J, Badano J L, Mah A K, Beales P L, Davidson W S, Johnsen R C, Audeh M, Plasterk R H, Baillie D L, Katsanis N, Quarmby L M, Wicks S R, Leroux M R (2004). Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev, 18(13): 1630–1642

[20] Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, Beyer T, Janusch H, Hamann C, G�del M, M�ller K, Herbst M, Hornung M, Doerken M, K�ttgen M, Nitschke R, Igarashi P, Walz G, Kuehn E W (2010). Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat Cell Biol, 12(11): 1115–1122

[21] Boudeau J, Baas A F, Deak M, Morrice N A, Kieloch A, Schutkowski M, Prescott A R, Clevers H C, Alessi D R (2003). MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J, 22(19): 5102–5114

[22] Bradshaw N J, Christie S, Soares D C, Carlyle B C, Porteous D J, Millar J K (2009). NDE1 and NDEL1: multimerisation, alternate splicing and DISC1 interaction. Neurosci Lett, 449(3): 228–233

[23] Bradshaw N J, Soares D C, Carlyle B C, Ogawa F, Davidson-Smith H, Christie S, Mackie S, Thomson P A, Porteous D J, Millar J K (2011). PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. J Neurosci, 31(24): 9043–9054

[24] Brandon N J, Handford E J, Schurov I, Rain J C, Pelling M, Duran-Jimeniz B, Camargo L M, Oliver K R, Beher D, Shearman M S, Whiting P J (2004). Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci, 25(1): 42–55

[25] Breunig J J, Sarkisian M R, Arellano J I, Morozov Y M, Ayoub A E, Sojitra S, Wang B, Flavell R A, Rakic P, Town T (2008). Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc Natl Acad Sci USA, 105(35): 13127–13132

[26] Burdick K E, Kamiya A, Hodgkinson C A, Lencz T, DeRosse P, Ishizuka K, Elashvili S, Arai H, Goldman D, Sawa A, Malhotra A K (2008). Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding. Hum Mol Genet, 17(16): 2462–2473

[27] Camargo L M, Collura V, Rain J C, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert T P, Whiting P J, Brandon N J (2007). Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry, 12(1): 74–86

[28] Chen G, Sima J, Jin M, Wang K Y, Xue X J, Zheng W, Ding Y Q, Yuan X B (2008). Semaphorin-3A guides radial migration of cortical neurons during development. Nat Neurosci, 11(1): 36–44

[29] Chen Y M, Wang Q J, Hu H S, Yu P C, Zhu J, Drewes G, Piwnica-Worms H, Luo Z G (2006). Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity. Proc Natl Acad Sci USA, 103(22): 8534–8539

[30] Chiang C, Litingtung Y, Lee E, Young K E, Corden J L, Westphal H, Beachy P A (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature, 383(6599): 407–413

[31] Chilov D, Sinjushina N, Rita H, Taketo M M, Mäkelä T P, Partanen J (2011). Phosphorylated β-catenin localizes to centrosomes of neuronal progenitors and is required for cell polarity and neurogenesis in developing midbrain. Dev Biol, 357(1): 259–268

[32] Chizhikov V V, Davenport J, Zhang Q, Shih E K, Cabello O A, Fuchs J L, Yoder B K, Millen K J (2007). Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci, 27(36): 9780–9789

[33] Corbit K C, Aanstad P, Singla V, Norman A R, Stainier D Y, Reiter J F (2005). Vertebrate Smoothened functions at the primary cilium. Nature, 437(7061): 1018–1021

[34] Corbit K C, Shyer A E, Doedle W E, Gaulden J, Singla V, Reiter J F (2008). Kif3a constrains beta-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms (vol 10, pg 70, 2008). Nat Cell Biol, 10(4): 497–497

[35] Dammermann A, Pemble H, Mitchell B J, McLeod I, Yates J R 3rd, Kintner C, Desai A B, Oegema K (2009). The hydrolethalus syndrome protein HYLS-1 links core centriole structure to cilia formation. Genes Dev, 23(17): 2046–2059

[36] de Anda F C, Meletis K, Ge X, Rei D, Tsai L H (2010). Centrosome motility is essential for initial axon formation in the neocortex. J Neurosci, 30(31): 10391–10406

[37] de Anda F C, Pollarolo G, Da Silva J S, Camoletto P G, Feiguin F, Dotti C G (2005). Centrosome localization determines neuronal polarity. Nature, 436(7051): 704–708

[38] Dickson B J, Gilestro G F (2006). Regulation of commissural axon pathfinding by slit and its Robo receptors. Annu Rev Cell Dev Biol, 22(1): 651–675

[39] Distel M, Hocking J C, Volkmann K, K�ster R W (2010). The centrosome neither persistently leads migration nor determines the site of axonogenesis in migrating neurons in vivo. J Cell Biol, 191(4): 875–890

[40] Duan X, Chang J H, Ge S, Faulkner R L, Kim J Y, Kitabatake Y, Liu X B, Yang C H, Jordan J D, Ma D K, Liu C Y, Ganesan S, Cheng H J, Ming G L, Lu B, Song H (2007). Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 130(6): 1146–1158

[41] Einstein E B, Patterson C A, Hon B J, Regan K A, Reddi J, Melnikoff D E, Mateer M J, Schulz S, Johnson B N, Tallent M K (2010). Somatostatin signaling in neuronal cilia is critical for object recognition memory. J Neurosci, 30(12): 4306–4314

[42] Ekker S C, Ungar A R, Greenstein P, von Kessler D P, Porter J A, Moon R T, Beachy P A (1995). Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Curr Biol, 5(8): 944–955

[43] Etienne-Manneville S, Hall A (2001). Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell, 106(4): 489–498

[44] Etienne-Manneville S, Hall A (2003). Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature, 421(6924): 753–756

[45] Faulkner R L, Jang M H, Liu X B, Duan X, Sailor K A, Kim J Y, Ge S, Jones E G, Ming G L, Song H, Cheng H J (2008). Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA, 105(37): 14157–14162

[46] Feng Y, Olson E C, Stukenberg P T, Flanagan L A, Kirschner M W, Walsh C A (2000). LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron, 28(3): 665–679

[47] Feng Y Y, Walsh C A (2004). Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron, 44(2): 279–293

[48] Fliegauf M, Benzing T, Omran H (2007). When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol, 8(11): 880–893

[49] Fukuda T, Sugita S, Inatome R, Yanagi S (2010). CAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration. J Biol Chem, 285(52): 40554–40561

[50] Gao W Q, Hatten M E (1993). Neuronal differentiation rescued by implantation of Weaver granule cell precursors into wild-type cerebellar cortex. Science, 260(5106): 367–369

[51] Gardiner S L, Rieger R M (1980). Rudimentary cilia in muscle cells of annelids and echinoderms. Cell Tissue Res, 213(2): 247–252

[52] G�rtner A, Fornasiero E F, Munck S, Vennekens K, Seuntjens E, Huttner W B, Valtorta F, Dotti C G (2012). N-cadherin specifies first asymmetry in developing neurons. EMBO J, 31(8): 1893–1903

[53] Gon�alves J, Nolasco S, Nascimento R, Lopez Fanarraga M, Zabala J C, Soares H (2010). TBCCD1, a new centrosomal protein, is required for centrosome and Golgi apparatus positioning. EMBO Rep, 11(3): 194–200

[54] Goodrich L V, Scott M P (1998). Hedgehog and patched in neural development and disease. Neuron, 21(6): 1243–1257

[55] Gorivodsky M, Mukhopadhyay M, Wilsch-Braeuninger M, Phillips M, Teufel A, Kim C, Malik N, Huttner W, Westphal H (2009). Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. Dev Biol, 325(1): 24–32

[56] Gupta S K, Meiri K F, Mahfooz K, Bharti U, Mani S (2010). Coordination between extrinsic extracellular matrix cues and intrinsic responses to orient the centrosome in polarizing cerebellar granule neurons. J Neurosci, 30(7): 2755–2766

[57] Han Y G, Spassky N, Romaguera-Ros M, Garcia-Verdugo J M, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A (2008). Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci, 11(3): 277–284

[58] H�ndel M, Schulz S, Stanarius A, Schreff M, Erdtmann-Vourliotis M, Schmidt H, Wolf G, H�llt V (1999). Selective targeting of somatostatin receptor 3 to neuronal cilia. Neuroscience, 89(3): 909–926

[59] Hatanaka Y, Murakami F (2002). In vitro analysis of the origin, migratory behavior, and maturation of cortical pyramidal cells. J Comp Neurol, 454(1): 1–14

[60] Hatten M E (2005). LIS-less neurons don’t even make it to the starting gate. J Cell Biol, 170(6): 867–871

[61] Haycraft C J, Banizs B, Aydin-Son Y, Zhang Q, Michaud E J, Yoder B K (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet, 1(4): e53

[62] Higginbotham H, Tanaka T, Brinkman B C, Gleeson J G (2006). GSK3beta and PKCzeta function in centrosome localization and process stabilization during Slit-mediated neuronal repolarization. Mol Cell Neurosci, 32(1-2): 118–132

[63] Higginbotham H R, Gleeson J G (2007). The centrosome in neuronal development. Trends Neurosci, 30(6): 276–283

[64] Hinds J W, Hinds P L (1978). Early development of amacrine cells in the mouse retina: an electron microscopic, serial section analysis. J Comp Neurol, 179(2): 277–300

[65] Ho K S, Scott M P (2002). Sonic hedgehog in the nervous system: functions, modifications and mechanisms. Curr Opin Neurobiol, 12(1): 57–63

[66] Hu H Y (1999). Chemorepulsion of neuronal migration by Slit2 in the developing mammalian forebrain. Neuron, 23(4): 703–711

[67] Huangfu D, Liu A, Rakeman A S, Murcia N S, Niswander L, Anderson K V (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 426(6962): 83–87

[68] Iba�ez-Tallon I, Pagenstecher A, Fliegauf M, Olbrich H, Kispert A, Ketelsen U P, North A, Heintz N, Omran H (2004). Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet, 13(18): 2133–2141

[69] Inagaki N, Chihara K, Arimura N, M�nager C, Kawano Y, Matsuo N, Nishimura T, Amano M, Kaibuchi K (2001). CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci, 4(8): 781–782

[70] Ishikawa H, Marshall W F (2011). Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol, 12(4): 222–234

[71] Ishizuka K, Kamiya A, Oh E C, Kanki H, Seshadri S, Robinson J F, Murdoch H, Dunlop A J, Kubo K, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay M D, Katsanis N, Sawa A (2011). DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature, 473(7345): 92–96

[72] Jacob L S, Wu X, Dodge M E, Fan C W, Kulak O, Chen B, Tang W, Wang B, Amatruda J F, Lum L (2011). Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Sci Signal, 4(157): ra4

[73] Jiang H, Guo W, Liang X, Rao Y (2005). Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell, 120(1): 123–135

[74] Jin H, White S R, Shida T, Schulz S, Aguiar M, Gygi S P, Bazan J F, Nachury M V (2010). The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell, 141(7): 1208–1219

[75] Juric-Sekhar G, Adkins J, Doherty D, Hevner R F (2012). Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia. Acta Neuropathol, 123(5): 695–709

[76] Kamiya A, Kubo K i, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross C A, Hatten M E, Nakajima K, Sawa A (2005). A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol, 7(12): 1167–1178

[77] Kamiya A, Tan P L, Kubo K, Engelhard C, Ishizuka K, Kubo A, Tsukita S, Pulver A E, Nakajima K, Cascella N G, Katsanis N, Sawa A (2008). Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Arch Gen Psychiatry, 65(9): 996–1006

[78] Killeen M T, Sybingco S S (2008). Netrin, Slit and Wnt receptors allow axons to choose the axis of migration. Dev Biol, 323(2): 143–151

[79] Kim J C, Badano J L, Sibold S, Esmail M A, Hill J, Hoskins B E, Leitch C C, Venner K, Ansley S J, Ross A J, Leroux M R, Katsanis N, Beales P L (2004). The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet, 36(5): 462–470

[80] Kishi M, Pan Y A, Crump J G, Sanes J R (2005). Mammalian SAD kinases are required for neuronal polarization. Science, 307(5711): 929–932

[81] Koizumi H, Tanaka T, Gleeson J G (2006). Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration. Neuron, 49(1): 55–66

[82] Komuro H, Yacubova E (2001). Mode and tempo of tangential cell migration in the cerebellar external granular layer. The Journal of neuroscience, 21(2): 527–540

[83] Kozminski K G, Johnson K A, Forscher P, Rosenbaum J L (1993). A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc Natl Acad Sci USA, 90(12): 5519–5523

[84] Kriegstein A, Alvarez-Buylla A (2009). The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci, 32(1): 149–184

[85] Kumamoto, N.Gu, Y., (2012). A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci, 15(3): 399–405, S391

[86] Kvajo M, McKellar H, Arguello P A, Drew L J, Moore H, MacDermott A B, Karayiorgou M, Gogos J A (2008). A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci USA, 105(19): 7076–7081

[87] Lancaster M A, Gleeson J G (2009). The primary cilium as a cellular signaling center: lessons from disease. Curr Opin Genet. Dev, 19(3): 220–229

[88] Lee J E, Gleeson J G (2011). Cilia in the nervous system: linking cilia function and neurodevelopmental disorders. Curr Opin Neurol, 24(2): 98–105

[89] Li J, Lee W L, Cooper J A (2005). NudEL targets dynein to microtubule ends through LIS1. Nat Cell Biol, 7(7): 686–690

[90] Lienkamp S, Ganner A, Walz G (2012). Inversin, Wnt signaling and primary cilia. Differentiation, 83(2): S49–S55

[91] Louvi A, Grove E A (2011). Cilia in the CNS: the quiet organelle claims center stage. Neuron, 69(6): 1046–1060

[92] Mao Y W, Ge X C, Frank C L, Madison J M, Koehler A N, Doud M K, Tassa C, Berry E M, Soda T, Singh K K, Biechele T, Petryshen T L, Moon R T, Haggarty S J, Tsai L H (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell, 136(6): 1017–1031

[93] McAllister A K (2002). Conserved cues for axon and dendrite growth in the developing cortex. Neuron, 33(1): 2–4

[94] Millar J K, Christie S, Porteous D J (2003). Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun, 311(4): 1019–1025

[95] Mirzadeh Z, Han Y G, Soriano-Navarro M, Garc�a-Verdugo J M, Alvarez-Buylla A (2010). Cilia organize ependymal planar polarity. J Neurosci, 30(7): 2600–2610

[96] Morgan J L, Dhingra A, Vardi N, Wong R O (2006). Axons and dendrites originate from neuroepithelial-like processes of retinal bipolar cells. Nat Neurosci, 9(1): 85–92

[97] Morris J A, Kandpal G, Ma L, Austin C P (2003). DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet, 12(13): 1591–1608

[98] Nachury M V, Loktev A V, Zhang Q, Westlake C J, Per�nen J, Merdes A, Slusarski D C, Scheller R H, Bazan J F, Sheffield V C, Jackson P K (2007). A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 129(6): 1201–1213

[99] Noctor S C, Mart�nez-Cerde�o V, Ivic L, Kriegstein A R (2004). Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci, 7(2): 136–144

[100] Ocbina P J, Dizon M L V, Shin L, Szele F G (2006). Doublecortin is necessary for the migration of adult subventricular zone cells from neurospheres. Mol Cell Neurosci, 33(2): 126–135

[101] Olbrich H, H�ffner K, Kispert A, V�lkel A, Volz A, Sasmaz G, Reinhardt R, Hennig S, Lehrach H, Konietzko N, Zariwala M, Noone P G, Knowles M, Mitchison H M, Meeks M, Chung E M, Hildebrandt F, Sudbrak R, Omran H (2002). Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet, 30(2): 143–144

[102] Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten M E, Snyder S H, Ross C A, Sawa A (2003). Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA, 100(1): 289–294

[103] Palazzo A F, Joseph H L (2001). Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Current biology, CB 11(19): 1536–1541

[104] Pazour G J, Dickert B L, Vucica Y, Seeley E S, Rosenbaum J L, Witman G B, Cole D G (2000). Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol, 151(3): 709–718

[105] Pazour G J, Witman G B (2003). The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol, 15(1): 105–110

[106] Pedersen L B, Rosenbaum J L (2008). Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol, 85: 23–61

[107] Phillips C L, Miller K J, Filson A J, N�rnberger J, Clendenon J L, Cook G W, Dunn K W, Overbeek P A, Gattone V H 2nd, Bacallao R L (2004). Renal cysts of inv/inv mice resemble early infantile nephronophthisis. J Am Soc Nephrol, 15(7): 1744–1755

[108] Polleux F, Giger R J, Ginty D D, Kolodkin A L, Ghosh A (1998). Patterning of cortical efferent projections by semaphorin-neuropilin interactions. Science, 282(5395): 1904–1906

[109] Polleux F, Morrow T, Ghosh A (2000). Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature, 404(6778): 567–573

[110] Raftopoulou M, Hall A (2004). Cell migration: Rho GTPases lead the way. Dev Biol, 265(1): 23–32

[111] Rakic P (1971). Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in Macacus Rhesus. J Comp Neurol, 141(3): 283–312

[112] Rakic P (1972). Mode of cell migration to the superficial layers of fetal monkey neocortex. J Comp Neurol, 145(1): 61–83

[113] Randlett O, Poggi L, Zolessi F R, Harris W A (2011). The oriented emergence of axons from retinal ganglion cells is directed by laminin contact inβvivo. Neuron, 70(2): 266–280

[114] Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836): 372–376

[115] Ross A J, May-Simera H, Eichers E R, Kai M, Hill J, Jagger D J, Leitch C C, Chapple J P, Munro P M, Fisher S, Tan P L, Phillips H M, Leroux M R, Henderson D J, Murdoch J N, Copp A J, Eliot M M, Lupski J R, Kemp D T, Dollfus H, Tada M, Katsanis N, Forge A, Beales P L (2005). Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet, 37(10): 1135–1140

[116] Saito T, Nakatsuji N (2001). Efficient gene transfer into the embryonic mouse brain using in vivo electroporation. Dev Biol, 240(1): 237–246

[117] Salathe M (2007). Regulation of mammalian ciliary beating. Annu Rev Physiol, 69(1): 401–422

[118] Sapir T, Sapoznik S(2008). Accurate balance of the polarity kinase MARK2/Par-1 is required for proper cortical neuronal migration. The Journal of neuroscience, 28(22): 5710–5720

[119] Sapir T, Shmueli A (2008). Antagonistic effects of doublecortin and MARK2/Par-1 in the developing cerebral cortex. The Journal of neuroscience, 28(48): 13008–13013.

[120] Schneider L, Clement C A, Teilmann S C, Pazour G J, Hoffmann E K, Satir P, Christensen S T (2005). PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr Biol, 15(20): 1861–1866

[121] Shelly M, Cancedda L, Heilshorn S, Sumbre G, Poo M M (2007). LKB1/STRAD promotes axon initiation during neuronal polarization. Cell, 129(3): 565–577

[122] Shi S-H, Cheng T (2004). APC and GSK-3beta are involved in mPar3 targeting to the nascent axon and establishment of neuronal polarity. Curr Biol, CB 14(22): 2025–2032

[123] Shi S H, Jan L Y, Jan Y N (2003). Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell, 112(1): 63–75

[124] Shiba D, Yamaoka Y, Hagiwara H, Takamatsu T, Hamada H, Yokoyama T (2009). Localization of Inv in a distinctive intraciliary compartment requires the C-terminal ninein-homolog-containing region. J Cell Sci, 122(Pt 1): 44–54

[125] Shoukimas G M, Hinds J W (1978). The development of the cerebral cortex in the embryonic mouse: an electron microscopic serial section analysis. J Comp Neurol, 179(4): 795–830

[126] Shu T Z, Ayala R, Nguyen M D, Xie Z, Gleeson J G, Tsai L H (2004). Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron, 44(2): 263–277

[127] Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Kr�nig C, Schermer B, Benzing T, Cabello O A, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G (2005). Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet, 37(5): 537–543

[128] Spassky N, Han Y G, Aguilar A, Strehl L, Besse L, Laclef C, Ros M R, Garcia-Verdugo J M, Alvarez-Buylla A (2008). Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol, 317(1): 246–259

[129] Stiess M, Maghelli N, Kapitein L C, Gomis-Rüth S, Wilsch-Bräuninger M, Hoogenraad C C, Tolić-Nørrelykke I M, Bradke F (2010). Axon extension occurs independently of centrosomal microtubule nucleation. Science, 327(5966): 704–707

[130] Stottmann R W, Tran P V, Turbe-Doan A, Beier D R (2009). Ttc21b is required to restrict sonic hedgehog activity in the developing mouse forebrain. Dev Biol, 335(1): 166–178

[131] Tanaka T, Serneo F F, Higgins C, Gambello M J, Wynshaw-Boris A, Gleeson J G (2004). Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol, 165(5): 709–721

[132] Taya S, Shinoda T (2007). DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. The Journal of neuroscience, 27(1): 15–26

[133] Taya S, Shinoda T, Tsuboi D, Asaki J, Nagai K, Hikita T, Kuroda S, Kuroda K, Shimizu M, Hirotsune S, Iwamatsu A, Kaibuchi K (2007). DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci, 27(1): 15–26

[134] Teichmann H M, Shen K (2011). UNC-6 and UNC-40 promote dendritic growth through PAR-4 in Caenorhabditis elegans neurons. Nat Neurosci, 14(2): 165–172

[135] ten Donkelaar H J, Hoevenaars F, Wesseling P (2000). A case of Joubert’s syndrome with extensive cerebral malformations. Clin Neuropathol, 19(2): 85–93

[136] Tsai J W, Chen Y, Kriegstein A R, Vallee R B (2005). LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J Cell Biol, 170(6): 935–945

[137] Tsai L H, Gleeson J G (2005). Nucleokinesis in neuronal migration. Neuron, 46(3): 383–388

[138] Umeshima H, Hirano T, Kengaku M (2007). Microtubule-based nuclear movement occurs independently of centrosome positioning in migrating neurons. Proc Natl Acad Sci USA, 104(41): 16182–16187

[139] Vergnolle M A S, Taylor S S (2007). Cenp-F links kinetochores to Ndel1/Nde1/Lis1/dynein microtubule motor complexes. Curr Biol, 17(13): 1173–1179

[140] Wallingford J B (2010). Planar cell polarity signaling, cilia and polarized ciliary beating. Curr Opin Cell Biol, 22(5): 597–604

[141] Wheatley D N (2005). Landmarks in the first hundred years of primary (9+0) cilium research. Cell Biol Int, 29(5): 333–339

[142] Wiens C J, Tong Y F, Esmail M A, Oh E, Gerdes J M, Wang J, Tempel W, Rattner J B, Katsanis N, Park H W, Leroux M R (2010). Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem, 285(21): 16218–16230

[143] Willaredt M A, Hasenpusch-Theil K, Gardner H A, Kitanovic I, Hirschfeld-Warneken V C, Gojak C P, Gorgas K, Bradford C L, Spatz J, W�lfl S, Theil T, Tucker K L (2008). A crucial role for primary cilia in cortical morphogenesis. J Neurosci, 28(48): 12887–12900

[144] Wong K, Ren X R, Huang Y Z, Xie Y, Liu G, Saito H, Tang H, Wen L, Brady-Kalnay S M, Mei L, Wu J Y, Xiong W C, Rao Y (2001). Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit-Robo pathway. Cell, 107(2): 209–221

[145] Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu J Y, Rao Y (1999). Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature, 400(6742): 331–336

[146] Xiang X (2003). LIS1 at the microtubule plus end and its role in dynein-mediated nuclear migration. J Cell Biol, 160(3): 289–290

[147] Yamada M, Toba S, Yoshida Y, Haratani K, Mori D, Yano Y, Mimori-Kiyosue Y, Nakamura T, Itoh K, Fushiki S, Setou M, Wynshaw-Boris A, Torisawa T, Toyoshima Y Y, Hirotsune S (2008). LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein. EMBO J, 27(19): 2471–2483

[148] Ylikorkala A, Rossi D J, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, M�kel� T P (2001). Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science, 293(5533): 1323–1326

[149] Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005). GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell, 120(1): 137–149

[150] Yuan S A L, Li J D, Diener D R, Choma M A, Rosenbaum J L, Sun Z (2012). Target-of-rapamycin complex 1 (Torc1) signaling modulates cilia size and function through protein synthesis regulation. Proc Natl Acad Sci USA, 109(6): 2021–2026

[151] Zaghloul N A, Katsanis N (2009). Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest, 119(3): 428–437

[152] Zhang Q H, Seo S, Bugge K, Stone E M, Sheffield V C (2012). BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Hum Mol Genet, 21(9): 1945–1953

[153] Zmuda J F, Rivas R J (1998). The Golgi apparatus and the centrosome are localized to the sites of newly emerging axons in cerebellar granule neurons in vitro. Cell Motil Cytoskeleton, 41(1): 18–38

[154] Zmuda J F, Rivas R J (2000). Actin filament disruption blocks cerebellar granule neurons at the unipolar stage of differentiation in vitro. J Neurobiol, 43(4): 313–328

[155] Zolessi F R, Poggi L, Wilkinson C J, Chien C B, Harris W A (2006). Polarization and orientation of retinal ganglion cells in vivo. Neural Dev, 1(1): 2

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