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The Neurodevelopmental Implications of PI3K Signaling

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Book cover Phosphoinositide 3-kinase in Health and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 346))

Abstract

Our understanding of the mechanisms involved in the formation of the complex arrangement of neurons and their interconnections within the brain has made significant progress in recent years. Current research has uncovered a network of intracellular signaling events that provide precise coordination of a diverse array of cellular responses, including trafficking events, cytoskeletal remodeling, gene transcription, and protein ubiquitination and translation. This chapter considers the specific cellular responses controlled by the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is instructive with regard to a number of important steps involved in the development of the brain. These range from the mediation of extrinsic signals – such as growth factors, axon guidance cues, and extracellular matrix components – to intrinsic effectors, such as downstream signaling components that act, for example, at the translation level. PI3K signaling is, consequently, at the heart of controlling neuronal migration and neuronal morphogenesis, as well as dendrite and synapse development. Many neurobehavioral disorders arise as a consequence of subtle developmental abnormalities. Unsurprisingly, therefore, aberrant PI3K signaling has been indicated by many studies to be a contributing factor to the pathophysiology of disorders such as schizophrenia and autism. In this chapter, we will focus on the specific, yet divergent, cellular processes that are achieved through PI3K signaling in neurons and are key to brain development.

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References

  • Arendt KL, Royo M, Fernandez-Monreal M, Knafo S, Petrok CN, Martens JR, Esteban, JA (2010) PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane. Nat Neurosci 13:36–44

    Google Scholar 

  • Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:341–355

    Article  PubMed  CAS  Google Scholar 

  • Acosta-Martinez M, Luo J, Elias C, Wolfe A, Levine JE (2009) Male-biased effects of gonadotropin-releasing hormone neuron-specific deletion of the phosphoinositide 3-kinase regulatory subunit p85{alpha} on the reproductive axis. Endocrinology 150:4203–4212

    Article  PubMed  CAS  Google Scholar 

  • Adler CE, Fetter RD, Bargmann CI (2006) UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation. Nat Neurosci 9:511–518

    Article  PubMed  CAS  Google Scholar 

  • Andersen BB, Pakkenberg B (2003) Stereological quantitation in cerebella from people with schizophrenia. Br J Psychiatry 182:354–361

    Article  PubMed  Google Scholar 

  • Andreasen NC (1995) Symptoms, signs, and diagnosis of schizophrenia. Lancet 346:477–481

    Article  PubMed  CAS  Google Scholar 

  • Arevalo MA, Rodriguez-Tebar A (2006) Activation of casein kinase II and inhibition of phosphatase and tensin homologue deleted on chromosome 10 phosphatase by nerve growth factor/p75NTR inhibit glycogen synthase kinase-3beta and stimulate axonal growth. Mol Biol Cell 17:3369–3377

    Article  PubMed  CAS  Google Scholar 

  • Arguello PA, Gogos JA (2008) A signaling pathway AKTing up in schizophrenia. J Clin Invest 118:2018–2021

    PubMed  CAS  Google Scholar 

  • Arimura N, Kaibuchi K (2005) Key regulators in neuronal polarity. Neuron 48:881–884

    Article  PubMed  CAS  Google Scholar 

  • Asano E, Chugani DC, Muzik O, Behen M, Janisse J, Rothermel R, Mangner TJ, Chakraborty PK, Chugani HT (2001) Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 57:1269–1277

    Article  PubMed  CAS  Google Scholar 

  • Atwal JK, Singh KK, Tessier-Lavigne M, Miller FD, Kaplan DR (2003) Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse. J Neurosci 23:7602–7609

    PubMed  CAS  Google Scholar 

  • Beaulieu JM, Gainetdinov RR, Caron MG (2007) The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol Sci 28:166–172

    Article  PubMed  CAS  Google Scholar 

  • Beffert U, Morfini G, Bock HH, Reyna H, Brady ST, Herz J (2002) Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3β. J Biol Chem 277:49958–49964

    Article  PubMed  CAS  Google Scholar 

  • Bock HH, Jossin Y, Liu P, Förster E, May P, Goffinet AM, Herz J (2003) Phosphatidylinositol 3-Kinase interacts with the adaptor protein Dab1 in response to Reelin signaling and is required for normal cortical lamination. J Biol Chem 278:38772–38779

    Article  PubMed  CAS  Google Scholar 

  • Brandt N, Franke K, Rasin MR, Baumgart J, Vogt J, Khrulev S, Hassel B, Pohl EE, Sestan N, Nitsch R et al (2007) The neural EGF family member CALEB/NGC mediates dendritic tree and spine complexity. EMBO J 26:2371–2386

    Article  PubMed  CAS  Google Scholar 

  • Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R et al (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42:318–321

    Article  PubMed  CAS  Google Scholar 

  • Chadborn NH, Ahmed AI, Holt MR, Prinjha R, Dunn GA, Jones GE, Eickholt BJ (2006) PTEN couples Sema3A signalling to growth cone collapse. J Cell Sci 119:951–957

    Article  PubMed  CAS  Google Scholar 

  • Chai X, Forster E, Zhao S, Bock HH, Frotscher M (2009) Reelin stabilizes the actin cytoskeleton of neuronal processes by inducing n-cofilin phosphorylation at serine3. J Neurosci 29:288–299

    Article  PubMed  CAS  Google Scholar 

  • Chen E, Finkel T (2009) Preview. The Tortoise, the hare, and the FoxO. Cell Stem Cell 5:451–452

    Article  PubMed  CAS  Google Scholar 

  • Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13:36–64

    Article  PubMed  CAS  Google Scholar 

  • Cosker KE, Eickholt BJ (2007) Phosphoinositide 3-kinase signalling events controlling axonal morphogenesis. Biochem Soc Trans 35:207–210

    Article  PubMed  CAS  Google Scholar 

  • Courchesne E, Pierce K (2005) Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci 23:153–170

    Article  PubMed  Google Scholar 

  • Croslan DR, Schoell MC, Ford GD, Pulliam JV, Gates A, Clement CM, Harris AE, Ford BD (2008) Neuroprotective effects of neuregulin-1 on B35 neuronal cells following ischemia. Brain Res 1210:39–47

    Article  PubMed  CAS  Google Scholar 

  • Da Silva JS, Hasegawa T, Miyagi T, Dotti CG, Abad-Rodriguez J (2005) Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nat Neurosci 8:606–615

    Article  PubMed  CAS  Google Scholar 

  • Dan HC, Sun M, Yang L, Feldman RI, Sui X-M, Ou CC, Nellist M, Yeung RS, Halley DJJ, Nicosia SV et al (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364–35370

    Article  PubMed  CAS  Google Scholar 

  • Das M, Scappini E, Martin NP, Wong KA, Dunn S, Chen Y-J, Miller SLH, Domin J, O’Bryan JP (2007) Regulation of neuron survival through an intersectin-phosphoinositide 3′-kinase C2{beta}-AKT pathway. Mol Cell Biol 27:7906–7917

    Article  PubMed  CAS  Google Scholar 

  • de Vries P, Humphrey A, McCartney D, Prather P, Bolton P, Hunt A (2005) Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis. Eur Child Adolesc Psychiatry 14:183–190

    Article  PubMed  Google Scholar 

  • Di Segni A, Shaharabani E, Stein R, Pinkas-Kramarski R (2005) Neuregulins rescue PC12-ErbB-4 cells from cell death induced by beta-amyloid peptide: involvement of PI3K and PKC. J Mol Neurosci 26:57–69

    Article  PubMed  Google Scholar 

  • Di Segni A, Farin K, Pinkas-Kramarski R (2006) ErbB4 activation inhibits MPP+-induced cell death in PC12-ErbB4 cells: involvement of PI3K and Erk signaling. J Mol Neurosci 29:257–267

    Article  PubMed  Google Scholar 

  • Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK et al (2007) Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130:1146–1158

    Article  PubMed  CAS  Google Scholar 

  • Dupraz S, Grassi D, Bernis ME, Sosa L, Bisbal M, Gastaldi L, Jausoro I, Caceres A, Pfenninger KH, Quiroga S (2009) The TC10-Exo70 complex is essential for membrane expansion and axonal specification in developing neurons. J Neurosci 29:13292–13301

    Article  PubMed  CAS  Google Scholar 

  • Eickholt BJ (2002) An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J Cell Biol 157:211–217

    Article  PubMed  CAS  Google Scholar 

  • Eickholt BJ, Ahmed AI, Davies M, Papakonstanti EA, Pearce W, Starkey ML, Bilancio A, Need AC, Smith AJ, Hall SM et al (2007) Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase. PLoS One 2:e869

    Article  PubMed  CAS  Google Scholar 

  • Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA (2004) Convergent evidence for impaired AKT1-GSK3[beta] signaling in schizophrenia. Nat Genet 36:131–137

    Article  PubMed  CAS  Google Scholar 

  • Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  PubMed  CAS  Google Scholar 

  • Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M (2005) Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9:389–402

    Article  PubMed  CAS  Google Scholar 

  • Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K et al (2009) Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron 63:774–787

    Article  PubMed  CAS  Google Scholar 

  • Ernfors P, Merlio JP, Persson H (1992) Cells expressing mRNA for neurotrophins and their receptors during embryonic rat development. Eur J Neurosci 4:1140–1158

    Article  PubMed  Google Scholar 

  • Faulkner RL, Jang MH, Liu XB, Duan X, Sailor KA, Kim JY, Ge S, Jones EG, Ming GL, Song H et al (2008) Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA 105:14157–14162

    Article  PubMed  CAS  Google Scholar 

  • Fivaz M, Bandara S, Inoue T, Meyer T (2008) Robust neuronal symmetry breaking by Ras-triggered local positive feedback. Curr Biol 18:44–50

    Article  PubMed  CAS  Google Scholar 

  • Fombonne E, Roge B, Claverie J, Courty S, Fremolle J (1999) Microcephaly and macrocephaly in autism. J Autism Dev Disord 29:113–119

    Article  PubMed  CAS  Google Scholar 

  • Fraser MM, Bayazitov IT, Zakharenko SS, Baker SJ (2008) Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151:476–488

    Article  PubMed  CAS  Google Scholar 

  • Funderburk SF, Wang QJ, Yue Z (In Press) The Beclin 1-VPS34 complex – at the crossroads of autophagy and beyond. Trends Cell Biol, Corrected Proof

    Google Scholar 

  • Gallo G (2006) RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction. J Cell Sci 119:3413–3423

    Article  PubMed  CAS  Google Scholar 

  • Gallo G (2008) Semaphorin 3A inhibits ERM protein phosphorylation in growth cone filopodia through inactivation of PI3K. Dev Neurobiol 68:926–933

    Article  PubMed  CAS  Google Scholar 

  • Gambarotta G, Garzotto D, Destro E, Mautino B, Giampietro C, Cutrupi S, Dati C, Cattaneo E, Fasolo A, Perroteau I (2004) ErbB4 expression in neural progenitor cells (ST14A) is necessary to mediate neuregulin-1beta1-induced migration. J Biol Chem 279:48808–48816

    Article  PubMed  CAS  Google Scholar 

  • Geraldo S, Gordon-Weeks PR (2009) Cytoskeletal dynamics in growth-cone steering. J Cell Sci 122:3595–3604

    Article  PubMed  CAS  Google Scholar 

  • Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57:65–73

    Article  PubMed  CAS  Google Scholar 

  • Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF (2006) Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res 81:47–63

    Article  PubMed  Google Scholar 

  • Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP (2001) PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet 105:521–524

    Article  PubMed  CAS  Google Scholar 

  • Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJH, Okkenhaug K, Vanhaesebroeck B (2008) The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ. Proc Natl Acad Sci USA 105:8292–8297

    Article  PubMed  CAS  Google Scholar 

  • Gunnell D, Holly JMP (2004) Insulin-like growth factors, insulin resistance and schizophrenia. Br J Psychiatry 185:353–354

    Article  PubMed  CAS  Google Scholar 

  • Guo W, Jiang H, Gray V, Dedhar S, Rao Y (2007) Role of the integrin-linked kinase (ILK) in determining neuronal polarity. Dev Biol 306:457–468

    Article  PubMed  CAS  Google Scholar 

  • Guo AY, Sun J, Riley BP, Thiselton DL, Kendler KS, Zhao Z (2009) The dystrobrevin-binding protein 1 gene: features and networks. Mol Psychiatry 14:18–29

    Article  PubMed  CAS  Google Scholar 

  • Harrison PJ (1999) Brains at risk of schizophrenia. Lancet 353:3–4

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA (2005) Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25:372–383

    Article  PubMed  CAS  Google Scholar 

  • Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    Article  PubMed  CAS  Google Scholar 

  • Herbert MR (2005) Large brains in autism: the challenge of pervasive abnormality. Neuroscientist 11:417–440

    Article  PubMed  Google Scholar 

  • Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, Sanders HA, Kennedy DN, Caviness VS Jr (2004) Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 55:530–540

    Article  PubMed  Google Scholar 

  • Hong CJ, Huo SJ, Liao DL, Lee K, Wu JY, Tsai SJ (2004) Case-control and family-based association studies between the neuregulin 1 (Arg38Gln) polymorphism and schizophrenia. Neurosci Lett 366:158–161

    Article  PubMed  CAS  Google Scholar 

  • Horiguchi K, Hanada T, Fukui Y, Chishti AH (2006) Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J Cell Biol 174:425–436

    Article  PubMed  CAS  Google Scholar 

  • Hörsch D, Kahn CR (1999) Region-specific mRNA expression of phosphatidylinositol 3-kinase regulatory isoforms in the central nervous system of C57BL/6J mice. J Comp Neurol 415:105–120

    Article  PubMed  Google Scholar 

  • Howlett E, Lin CC, Lavery W, Stern M (2008) A PI3-kinase-mediated negative feedback regulates neuronal excitability. PLoS Genet 4:e1000277

    Article  PubMed  CAS  Google Scholar 

  • Inoki K, Li Y, Zhu T, Wu J, Guan K-L (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657

    Article  PubMed  CAS  Google Scholar 

  • Ito Y, Goto K, Kondo H (1995) Localization of mRNA for phosphatidylinositol 3-kinase in brain of developing and mature rats. Brain Res Mol Brain Res 34:149–153

    Article  PubMed  CAS  Google Scholar 

  • Ito Y, Oinuma I, Katoh H, Kaibuchi K, Negishi M (2006) Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. EMBO Rep 7:704–709

    Article  PubMed  CAS  Google Scholar 

  • Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137

    Article  PubMed  CAS  Google Scholar 

  • Jan YN, Jan LY (2003) The control of dendrite development. Neuron 40:229–242

    Article  PubMed  CAS  Google Scholar 

  • Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M (2005) Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 25:11300–11312

    Article  PubMed  CAS  Google Scholar 

  • Jossin Y, Goffinet AM (2007) Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth. Mol Cell Biol 27:7113–7124

    Article  PubMed  CAS  Google Scholar 

  • Kalkman HO (2006) The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol Ther 110:117–134

    Article  PubMed  CAS  Google Scholar 

  • Kalus P, Muller TJ, Zuschratter W, Senitz D (2000) The dendritic architecture of prefrontal pyramidal neurons in schizophrenic patients. Neuroreport 11:3621–3625

    Article  PubMed  CAS  Google Scholar 

  • Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M et al (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7:1167–1178

    Article  PubMed  CAS  Google Scholar 

  • Kamiya A, Tomoda T, Chang J, Takaki M, Zhan C, Morita M, Cascio MB, Elashvili S, Koizumi H, Takanezawa Y et al (2006) DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet 15:3313–3323

    Article  PubMed  CAS  Google Scholar 

  • Kim JY, Duan X, Liu CY, Jang MH, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming GL (2009) DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron 63:761–773

    Article  PubMed  CAS  Google Scholar 

  • Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Preuss TM, Wohlschlegel JA, Geschwind DH (2009) Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462:213–217

    Article  PubMed  CAS  Google Scholar 

  • Krause M, Leslie JD, Stewart M, Lafuente EM, Valderrama F, Jagannathan R, Strasser GA, Rubinson DA, Liu H, Way M et al (2004) Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Dev Cell 7:571–583

    Article  PubMed  CAS  Google Scholar 

  • Kreis P, van Diepen MT, Eickholt BJ (2009) Regulation of PTEN in neurons by myosin-based transport mechanisms. Adv Enzyme Regul 50:119–124

    Article  PubMed  Google Scholar 

  • Kumar V, Zhang MX, Swank MW, Kunz J, Wu GY (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25:11288–11299

    Article  PubMed  CAS  Google Scholar 

  • Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF (2006a) Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–388

    Article  PubMed  CAS  Google Scholar 

  • Kwon CH, Zhou J, Li Y, Kim KW, Hensley LL, Baker SJ, Parada LF (2006b) Neuron-specific enolase-cre mouse line with cre activity in specific neuronal populations. Genesis 44:130–135

    Article  PubMed  CAS  Google Scholar 

  • Landa R, Garrett-Mayer E (2006) Development in infants with autism spectrum disorders: a prospective study. J Child Psychol Psychiatry 47:629–638

    Article  PubMed  Google Scholar 

  • Leslie NR, Maccario H, Spinelli L, Davidson L (2009) The significance of PTEN’s protein phosphatase activity. Adv Enzyme Regul 49:190–196

    Article  PubMed  CAS  Google Scholar 

  • Levitt P, Campbell DB (2009) The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest 119:747–754

    Article  PubMed  CAS  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Tennekoon GI, Birnbaum M, Marchionni MA, Rutkowski JL (2001) Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival. Mol Cell Neurosci 17:761–767

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Schulz SC, Lee S, Reutiman TJ, Fatemi SH (2007) Hippocampal CA1 pyramidal cell size is reduced in bipolar disorder. Cell Mol Neurobiol 27:351–358

    Article  PubMed  Google Scholar 

  • Liu YC, Huang CL, Wu PL, Chang YC, Huang CH, Lane HY (2009) Lack of association between AKT1 variances versus clinical manifestations and social function in patients with schizophrenia. J Psychopharmacol 23:937–943

    Article  PubMed  CAS  Google Scholar 

  • Luikart BW, Zhang W, Wayman GA, Kwon CH, Westbrook GL, Parada LF (2008) Neurotrophin-dependent dendritic filopodial motility: a convergence on PI3K signaling. J Neurosci 28:7006–7012

    Article  PubMed  CAS  Google Scholar 

  • Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D’Souza S, Wong TP, Taghibiglou C, Lu J et al (2003) Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 38:611–624

    Article  PubMed  CAS  Google Scholar 

  • Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK et al (2009) Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136:1017–1031

    Article  PubMed  CAS  Google Scholar 

  • McCaffery P, Deutsch CK (2005) Macrocephaly and the control of brain growth in autistic disorders. Prog Neurobiol 77:38–56

    Article  PubMed  Google Scholar 

  • Medina DL, Sciarretta C, Calella AM, von Bohlen und Halbach O, Unsicker K, Minichiello L (2004) TrkB regulates neocortex formation through the Shc/PLC[gamma]-mediated control of neuronal migration. EMBO J 23:3803–3814

    Article  PubMed  CAS  Google Scholar 

  • Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452

    Article  PubMed  CAS  Google Scholar 

  • Menager C, Arimura N, Fukata Y, Kaibuchi K (2004) PIP3 is involved in neuronal polarization and axon formation. J Neurochem 89:109–118

    Article  PubMed  CAS  Google Scholar 

  • Ming GL, Song H (2009) DISC1 partners with GSK3beta in neurogenesis. Cell 136:990–992

    Article  PubMed  CAS  Google Scholar 

  • Morita T, Sobue K (2009) Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem 284:27734–27745

    Article  PubMed  CAS  Google Scholar 

  • Narr KL, Bilder RM, Toga AW, Woods RP, Rex DE, Szeszko PR, Robinson D, Sevy S, Gunduz-Bruce H, Wang YP et al (2005a) Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cereb Cortex 15:708–719

    Article  PubMed  Google Scholar 

  • Narr KL, Toga AW, Szeszko P, Thompson PM, Woods RP, Robinson D, Sevy S, Wang Y, Schrock K, Bilder RM (2005b) Cortical thinning in cingulate and occipital cortices in first episode schizophrenia. Biol Psychiatry 58:32–40

    Article  PubMed  Google Scholar 

  • Norton N, Williams HJ, Dwyer S, Carroll L, Peirce T, Moskvina V, Segurado R, Nikolov I, Williams NM, Ikeda M et al (2007) Association analysis of AKT1 and schizophrenia in a UK case control sample. Schizophr Res 93:58–65

    Article  PubMed  Google Scholar 

  • Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, Ozaki N, Taguchi T, Tatsumi M, Kamijima K et al (2004) Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet 13:2699–2708

    Article  PubMed  CAS  Google Scholar 

  • Odorizzi G, Babst M, Emr SD (2000) Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem Sci 25:229–235

    Article  PubMed  CAS  Google Scholar 

  • Ohkubo N, Vitek MP, Morishima A, Suzuki Y, Miki T, Maeda N, Mitsuda N (2007) Reelin signals survival through Src-family kinases that inactivate BAD activity. J Neurochem 103:820–830

    Article  PubMed  CAS  Google Scholar 

  • Oinuma I, Katoh H, Negishi M (2007) R-Ras controls axon specification upstream of glycogen synthase kinase-3beta through integrin-linked kinase. J Biol Chem 282:303–318

    Article  PubMed  CAS  Google Scholar 

  • Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V (2009) Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet 75:195–198

    Article  PubMed  CAS  Google Scholar 

  • Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K, Okawa M, Yamada N, Hatten ME, Snyder SH et al (2003) Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 100:289–294

    Article  PubMed  CAS  Google Scholar 

  • Paik JH, Ding Z, Narurkar R, Ramkissoon S, Muller F, Kamoun WS, Chae SS, Zheng H, Ying H, Mahoney J et al (2009) FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5:540–553

    Article  PubMed  CAS  Google Scholar 

  • Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T et al (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53:703–717

    Article  PubMed  CAS  Google Scholar 

  • Persico AM, Bourgeron T (2006) Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 29:349–358

    Article  PubMed  CAS  Google Scholar 

  • Pietilainen OP, Paunio T, Loukola A, Tuulio-Henriksson A, Kieseppa T, Thompson P, Toga AW, van Erp TG, Silventoinen K, Soronen P et al (2009) Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins. Am J Med Genet B Neuropsychiatr Genet 150B:683–692

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Polleux F, Whitford KL, Dijkhuizen PA, Vitalis T, Ghosh A (2002) Control of cortical interneuron migration by neurotrophins and PI3-kinase signaling. Development 129:3147–3160

    PubMed  CAS  Google Scholar 

  • Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC et al (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5:527–539

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  • Schwamborn JC, Puschel AW (2004) The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7:923–929

    Article  PubMed  CAS  Google Scholar 

  • Schwamborn JC, Li Y, Puschel AW (2006) GTPases and the control of neuronal polarity. Methods Enzymol 406:715–727

    Article  PubMed  CAS  Google Scholar 

  • Segarra J, Balenci L, Drenth T, Maina F, Lamballe F (2006) Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration. J Biol Chem 281:4771–4778

    Article  PubMed  CAS  Google Scholar 

  • Selemon LD, Rajkowska G, Goldman-Rakic PS (1995) Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805–818, Discussion 819–820

    Article  PubMed  CAS  Google Scholar 

  • Shi SH, Jan LY, Jan YN (2003) Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112:63–75

    Article  PubMed  CAS  Google Scholar 

  • Shin BC, Suzuki M, Inukai K, Anai M, Asano T, Takata K (1998) Multiple isoforms of the regulatory subunit for phosphatidylinositol 3-kinase (PI3-kinase) are expressed in neurons in the rat brain. Biochem Biophys Res Commun 246:313–319

    Article  PubMed  CAS  Google Scholar 

  • Simonsen A, Tooze SA (2009) Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol 186:773–782

    Article  PubMed  CAS  Google Scholar 

  • Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Caceres A, Pfenninger KH, Quiroga S (2006) IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci 9:993–995

    Article  PubMed  CAS  Google Scholar 

  • Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    Article  PubMed  Google Scholar 

  • Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, Gunnarsdottir S, Walker N, Petursson H, Crombie C et al (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 72:83–87

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Thiselton DL, Vladimirov VI, Kuo PH, McClay J, Wormley B, Fanous A, O’Neill FA, Walsh D, Van den Oord EJ, Kendler KS et al (2008) AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. Biol Psychiatry 63:449–457

    Article  PubMed  CAS  Google Scholar 

  • Tohda C, Nakanishi R, Kadowaki M (2006) Learning deficits and agenesis of synapses and myelinated axons in phosphoinositide-3 kinase-deficient mice. Neurosignals 15:293–306

    Article  PubMed  CAS  Google Scholar 

  • Tohda C, Nakanishi R, Kadowaki M (2009) Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85alpha subunit of phosphoinositide-3 kinase. Brain Dev 31:69–74

    Article  PubMed  Google Scholar 

  • Toriyama M, Shimada T, Kim KB, Mitsuba M, Nomura E, Katsuta K, Sakumura Y, Roepstorff P, Inagaki N (2006) Shootin1: a protein involved in the organization of an asymmetric signal for neuronal polarization. J Cell Biol 175:147–157

    Article  PubMed  CAS  Google Scholar 

  • Tosato S, Dazzan P, Collier D (2005) Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophr Bull 31:613–617

    Article  PubMed  Google Scholar 

  • Trejo JL, Pons S (2001) Phosphatidylinositol-3-OH kinase regulatory subunits are differentially expressed during development of the rat cerebellum. J Neurobiol 47:39–50

    Article  PubMed  CAS  Google Scholar 

  • Tucker KL (2002) Neurotrophins and the control of axonal outgrowth. Panminerva Med 44:325–333

    PubMed  CAS  Google Scholar 

  • van Diepen MT, Eickholt BJ (2008) Function of PTEN during the formation and maintenance of neuronal circuits in the brain. Dev Neurosci 30:59–64

    Article  PubMed  CAS  Google Scholar 

  • van Diepen MT, Parsons M, Downes CP, Leslie NR, Hindges R, Eickholt BJ (2009) MyosinV controls PTEN function and neuronal cell size. Nat Cell Biol 11:1191–1196

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70:535–602

    Article  PubMed  CAS  Google Scholar 

  • Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, Fazzari P, Tamagnone L, Offermanns S, Kuner R (2009) The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. Eur J Neurosci 30:1193–1208

    Article  PubMed  Google Scholar 

  • Welch HC, Coadwell WJ, Stephens LR, Hawkins PT (2003) Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett 546:93–97

    Article  PubMed  CAS  Google Scholar 

  • Wiggin GR, Fawcett JP, Pawson T (2005) Polarity proteins in axon specification and synaptogenesis. Dev Cell 8:803–816

    Article  PubMed  CAS  Google Scholar 

  • Wiznitzer M (2004) Autism and tuberous sclerosis. J Child Neurol 19:675–679

    PubMed  Google Scholar 

  • Yan D, Guo L, Wang Y (2006) Requirement of dendritic Akt degradation by the ubiquitin-proteasome system for neuronal polarity. J Cell Biol 174:415–424

    Article  PubMed  CAS  Google Scholar 

  • Yang F, He X, Feng L, Mizuno K, Liu XW, Russell J, Xiong WC, Lu B (2001) PI-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nat Neurosci 4:19–28

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura T, Arimura N, Kawano Y, Kawabata S, Wang S, Kaibuchi K (2006) Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. Biochem Biophys Res Commun 340:62–68

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ (2003) Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 112:1223–1233

    PubMed  CAS  Google Scholar 

  • Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD (2004) NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Neuron 42:897–912

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W, Sinton C, Powell CM, Parada LF (2009) Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 29:1773–1783

    Article  PubMed  CAS  Google Scholar 

  • Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443–455

    Article  PubMed  CAS  Google Scholar 

  • Zori RT, Marsh DJ, Graham GE, Marliss EB, Eng C (1998) Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 80:399–402

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded by the Medical Research Council (Ref G0802289). We thank Carl Hobbs for the immunohistochemistry staining of p110δ PI3K in the developing brain.

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  1. MRC Centre for Developmental Neurobiology, King’s College London, New Hunt’s House, London, SE1 1UL, UK

    Kathryn Waite & Britta J. Eickholt

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  1. Kathryn Waite
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  2. Britta J. Eickholt
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Correspondence to Britta J. Eickholt .

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  1. Intellikine, North Torreye Pines Road 10931, La Jolla, 92037, California, USA

    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

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Waite, K., Eickholt, B.J. (2010). The Neurodevelopmental Implications of PI3K Signaling. In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 346. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_82

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