Neuroscience Bulletin

, Volume 29, Issue 6, pp 773–778 | Cite as

Role of the PTEN signaling pathway in autism spectrum disorder

  • Jing-Wen Lv
  • Tian-Lin Cheng
  • Zi-Long Qiu
  • Wen-Hao Zhou
Review

Abstract

Autism is an etiologically heterogeneous group of neurodevelopmental disorders, diagnosed mostly by the clinical behavioral phenotypes. The concept that the tumor-related gene PTEN plays a critical role in autism spectrum disorder has emerged over the last decade. In this review, we focus on the essential role of the PTEN signaling pathway in neuronal differentiation and the formation of neural circuitry, as well as genetic mouse models with Pten manipulations. Particularly, accumulated data suggest that the effect of PTEN on neural stem-cell development contributes significantly to the pathophysiology of autism spectrum disorders.

Keywords

PTEN TSC1/2 autism synapse neural stem cells 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275(5308): 1943–1947.PubMedCrossRefGoogle Scholar
  2. [2]
    Endersby R, Baker SJ. PTEN signal ing in brain: neuropathology and tumorigenesis. Oncogene 2008, 27(41): 5416–5430.PubMedCrossRefGoogle Scholar
  3. [3]
    Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet 2008, 16(11): 1289–1300.PubMedCrossRefGoogle Scholar
  4. [4]
    Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet 2003, 12(6): 679–684.PubMedCrossRefGoogle Scholar
  5. [5]
    Inoki K, Li Y, Zhu T, Wu J, Guan K L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002, 4(9): 648–657.PubMedCrossRefGoogle Scholar
  6. [6]
    Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002, 10(1): 151–162.PubMedCrossRefGoogle Scholar
  7. [7]
    Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002, 4(9):658–665.PubMedCrossRefGoogle Scholar
  8. [8]
    Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 2010, 11(7): 490–502.PubMedCrossRefGoogle Scholar
  9. [9]
    Bertrand J, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, Decoufle P. Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics 2001, 108(5): 1155–1161.PubMedCrossRefGoogle Scholar
  10. [10]
    Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of autism in a US metropolitan area. JAMA 2003, 289(1): 49–55.PubMedCrossRefGoogle Scholar
  11. [11]
    Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord 2003, 33(4): 365–382.PubMedCrossRefGoogle Scholar
  12. [12]
    Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005, 42(4): 318–321.PubMedCrossRefGoogle Scholar
  13. [13]
    Smalley SL, Tanguay PE, Smith M, Gutierrez G. Autism and tuberous sclerosis. J Autism Dev Disord 1992, 22(3): 339–355.PubMedCrossRefGoogle Scholar
  14. [14]
    Smalley SL. Autism and tuberous sclerosis. J Autism Dev Disord 1998, 28(5): 407–414.PubMedCrossRefGoogle Scholar
  15. [15]
    Wiznitzer M. Autism and tuberous sclerosis. J Child Neurol 2004, 19(9): 675–679.PubMedGoogle Scholar
  16. [16]
    Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J, et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet B Neuropsychiatr Genet 2007, 144B(4): 484–491.PubMedCrossRefGoogle Scholar
  17. [17]
    Fombonne E, Du Mazaubrun C, Cans C, Grandjean H. Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997, 36(11): 1561–1569.PubMedGoogle Scholar
  18. [18]
    Baker P, Piven J, Sato Y. Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 1998, 28(4): 279–285.PubMedCrossRefGoogle Scholar
  19. [19]
    Asano E, Chugani DC, Muzik O, Behen M, Janisse J, Rothermel R, et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 2001, 57(7): 1269–1277.PubMedCrossRefGoogle Scholar
  20. [20]
    Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006, 50(3): 377–388.PubMedCrossRefGoogle Scholar
  21. [21]
    Jaworski J, Spangler S, Seeburg DP, Hoogenraad C C, Sheng M. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J Neurosci 2005, 25(49): 11300–11312.PubMedCrossRefGoogle Scholar
  22. [22]
    Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini B L. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J Neurosci 2011, 31(24): 8862–8869.PubMedCrossRefGoogle Scholar
  23. [23]
    Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, et al. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 2007, 27(21): 5546–5558.PubMedCrossRefGoogle Scholar
  24. [24]
    Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 2011, 20(3): 445–454.PubMedCrossRefGoogle Scholar
  25. [25]
    Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 2009, 11(2): 111–117.PubMedCrossRefGoogle Scholar
  26. [26]
    Zhou J, Parada LF. PTEN signaling in autism spectrum disorders. Curr Opin Neurobiol 2012, 22(5): 873–879.PubMedCrossRefGoogle Scholar
  27. [27]
    Bolton PF. Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Ment Retard Dev Disabil Res Rev 2004, 10(2): 126–131.PubMedCrossRefGoogle Scholar
  28. [28]
    Jeste SS, Sahin M, Bolton P, Ploubidis GB, Humphrey A. Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol 2008, 23(5): 520–525.PubMedCrossRefGoogle Scholar
  29. [29]
    Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack J A, et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 2001, 294(5549): 2186–2189.PubMedCrossRefGoogle Scholar
  30. [30]
    Gregorian C, Nakashima J, Le Belle J, Ohab J, Kim R, Liu A, et al. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis. J Neurosci 2009, 29(6): 1874–1886.PubMedCrossRefGoogle Scholar
  31. [31]
    Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, et al. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 2011, 145(7): 1142–1155.PubMedCrossRefGoogle Scholar
  32. [32]
    Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, et al. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J Neurosci 2012, 32(17): 5880–5890.PubMedCrossRefGoogle Scholar
  33. [33]
    Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 2009, 5(3): 279–289.PubMedCrossRefGoogle Scholar
  34. [34]
    Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S, et al. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci U S A 2011, 108(45): E1070–E1079.PubMedCrossRefGoogle Scholar
  35. [35]
    Magri L, Cambiaghi M, Cominelli M, Alfaro-Cervello C, Cursi M, Pala M, et al. Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 2011, 9(5): 447–462.PubMedCrossRefGoogle Scholar
  36. [36]
    Zhou J, Shrikhande G, Xu J, McKay RM, Burns DK, Johnson JE, et al. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 2011, 25(15): 1595–1600.PubMedCrossRefGoogle Scholar
  37. [37]
    Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 2001, 29(4): 396–403.PubMedCrossRefGoogle Scholar
  38. [38]
    Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, et al. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 2001, 29(4): 404–411.PubMedCrossRefGoogle Scholar
  39. [39]
    Marino S, Krimpenfort P, Leung C, van der Korput HA, Trapman J, Camenisch I, et al. PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development 2002, 129(14): 3513–3522.PubMedGoogle Scholar
  40. [40]
    Fraser MM, Zhu X, Kwon CH, Uhlmann EJ, Gutmann DH, Baker SJ. Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res 2004, 64(21): 7773–7779.PubMedCrossRefGoogle Scholar
  41. [41]
    Yue Q, Groszer M, Gil JS, Berk AJ, Messing A, Wu H, et al. PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development 2005, 132(14): 3281–3291.PubMedCrossRefGoogle Scholar
  42. [42]
    Jiang H, Guo W, Liang X, Rao Y. Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 2005, 120(1): 123–135.PubMedGoogle Scholar
  43. [43]
    Luikart BW, Schnell E, Washburn EK, Bensen AL, Tovar KR, Westbrook GL. Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J Neurosci 2011, 31(11): 4345–4354.PubMedCrossRefGoogle Scholar
  44. [44]
    Zhang XC, Piccini A, Myers MP, Van Aelst L, Tonks NK. Functional analysis of the protein phosphatase activity of PTEN. Biochem J 2012, 444(3): 457–464.PubMedCrossRefGoogle Scholar
  45. [45]
    Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 2005, 8(12): 1727–1734.PubMedCrossRefGoogle Scholar
  46. [46]
    Kelleher RR, Bear MF. The autistic neuron: troubled translation? Cell 2008, 135(3): 401–406.PubMedCrossRefGoogle Scholar
  47. [47]
    Chow DK, Groszer M, Pribadi M, Machniki M, Carmichael ST, Liu X, et al. Laminar and compartmental regulation of dendritic growth in mature cortex. Nat Neurosci 2009, 12(2): 116–118.PubMedCrossRefGoogle Scholar
  48. [48]
    Stiles B, Groszer M, Wang S, Jiao J, Wu H. PTENless means more. Dev Biol 2004, 273(2): 175–184.PubMedCrossRefGoogle Scholar
  49. [49]
    Li G, Robinson GW, Lesche R, Martinez-Diaz H, Jiang Z, Rozengurt N, et al. Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland. Development 2002, 129(17): 4159–4170.PubMedGoogle Scholar
  50. [50]
    Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001, 14(5): 523–534.PubMedCrossRefGoogle Scholar
  51. [51]
    Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 2002, 110(6): 737–749.PubMedCrossRefGoogle Scholar
  52. [52]
    Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 2008, 14(8):843–848.PubMedCrossRefGoogle Scholar
  53. [53]
    Ehninger D, Silva AJ. Increased levels of anxiety-related behaviors in a Tsc2 dominant negative transgenic mouse model of tuberous sclerosis. Behav Genet 2011, 41(3): 357–363.PubMedCrossRefGoogle Scholar
  54. [54]
    Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W, Sinton C, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neuralspecific Pten knock-out mice. J Neurosci 2009, 29(6): 1773–1783.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jing-Wen Lv
    • 1
  • Tian-Lin Cheng
    • 2
  • Zi-Long Qiu
    • 2
  • Wen-Hao Zhou
    • 1
  1. 1.Department of NeonatologyChildren’s Hospital of Fudan UniversityShanghaiChina
  2. 2.Institute of Neuroscience, Shanghai Institute of Biological SciencesChinese Academy of SciencesShanghaiChina

Personalised recommendations