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Above genetics: Lessons from cerebral development in autism

Translational Neuroscience volume 2, pages 106–120 (2011)Cite this article

Abstract

While a distinct minicolumnar phenotype seems to be an underlying factor in a significant portion of cases of autism, great attention is being paid not only to genetics but to epigenetic factors which may lead to development of the conditions. Here we discuss the indivisible role the molecular environment plays in cellular function, particularly the pivotal position which the transcription factor and adhesion molecule, β-catenin, occupies in cellular growth. In addition, the learning environment is not only integral to postnatal plasticity, but the prenatal environment plays a vital role during corticogenesis, neuritogenesis, and synaptogenesis as well. To illustrate these points in the case of autism, we review important findings in genetics studies (e.g., PTEN, TSC1/2, FMRP, MeCP2, Neurexin-Neuroligin) and known epigenetic factors (e.g., valproic acid, estrogen, immune system, ultrasound) which may predispose towards the minicolumnar and connectivity patterns seen in the conditions, showing how one-gene mutational syndromes and exposure to certain CNS teratogens may ultimately lead to comparable phenotypes. This in turn may shed greater light on how environment and complex genetics combinatorially give rise to a heterogenetic group of conditions such as autism.

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References

  1. Liu J., Nyholt D.R., Magnussen P., Parano E., Pavone P., Geschwind D., et al., A genomewide screen for autism susceptibility loci, Am. J. Hum. Genet., 2001, 69, 327–340

    PubMed  CAS  Google Scholar 

  2. Yonan A.L., Alarcón M., Cheng R, Magnusson P.K., Spence S.J., Palmer A.A., et al., A genomewide screen of 345 families for autism-susceptibility loci, Am. J. Hum. Genet., 2003, 73, 886–897

    PubMed  CAS  Google Scholar 

  3. Williams E.L., Casanova M.F., Autism or autisms? Finding the lowest common denominator, Bol. Asoc. Méd. P.R., 2010 Oct, 102(4), 17–24

    Google Scholar 

  4. Minshew N.J., Williams D.L., The new neurobiology of autism: Cortex, connectivity, and neuronal organization, Arch. Neurol., 2007, 64, 945–950

    PubMed  Google Scholar 

  5. Casanova M.F., Buxhoeveden D.P., Switala A.E., Roy E. Minicolumnar pathology in autism, Neurology, 2002, 58, 428–432

    PubMed  Google Scholar 

  6. Chenn A., Walsh C.A., Regulation of cerebral cortical size by control of cell cycle exit in neural precursors, Science, 2002, 297, 365–369

    PubMed  CAS  Google Scholar 

  7. Bauman M.L., Kemper T.L., Neuroanatomic observations of the brain in autism: A review and future directions, Int. J. Dev. Neurosci., 2005, 23, 183–187

    PubMed  Google Scholar 

  8. Herbert M.R., Ziegler D.A., Makris N., Filipek P.A., Kemper T.L., Normandin J.J., et al., Localization of white matter volume increase in autism and developmental language disorder, Ann. Neurol., 2004, 55, 530–540

    PubMed  Google Scholar 

  9. Rinaldi T., Kulangara K., Antoniello K., Markram H., Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13501–13506

    PubMed  CAS  Google Scholar 

  10. Rinaldi T., Perrodin C., Markram H., Hyper-connectivity and hyperplasticity in the medial prefrontal cortex in the valproic acid animal model of autism, Front. Neural Circuits, 2008, 2, 1–7

    Google Scholar 

  11. Casanova M.F., El-Baz A., Mott M., Mannheim G., Hassan H., Fahmi R., et al., Reduced gyral window and corpus callosum size in autism: Possible macroscopic correlates of a minicolumnopathy, J. Autism Dev. Disord., 2009, 39, 751–764

    PubMed  Google Scholar 

  12. Beaudet A.L., Autism: highly heritable but not inherited, Nat. Med., 2007, 13, 534–536

    PubMed  CAS  Google Scholar 

  13. Muhle R., Trentacoste S.V., Rapin I., The genetics of autism, Pediatrics, 2004, 113, e472–e486

    PubMed  Google Scholar 

  14. Herbert M.R., Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders, Curr. Opin. Neurol., 2010, 23, 103–110

    PubMed  Google Scholar 

  15. Courchesne E., Carper R., Akshoomoff N., Evidence of brain overgrowth in the first year of life in autism, J. Am. Med. Assoc., 2003, 290, 337–344

    Google Scholar 

  16. Rogers S.J., Developmental regression in autism spectrum disorders, Ment. Retard. Dev. Disabil. Res. Rev., 2004, 10, 139–143

    PubMed  Google Scholar 

  17. Kumar V., Zhang M.X., Swank M.W., Kunz J., Wu G.Y., Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways, J. Neurosci., 2005, 25, 11288–11299

    PubMed  CAS  Google Scholar 

  18. McDaniel M.A., Big-brained people are smarter: A meta-analysis of the relationship between in vivo brain volume and intelligence, Intelligence, 2005, 33, 337–346

    Google Scholar 

  19. Burrell B., Postcards from the brain museum, Broadway Books, New York, 2004

    Google Scholar 

  20. Happé F., Frith U., The weak central coherence account: Detail-focused cognitive style in autism spectrum disorders, J. Autism Dev. Disord., 2006, 36, 5–25

    PubMed  Google Scholar 

  21. Treffert D.A., Extraordinary people: Understanding savant syndrome, iUniverse, Lincoln, 2006

    Google Scholar 

  22. Redcay E., Courchesne E., When is the brain enlarged in autism? A meta-analysis of all brain size reports, Biol. Psychiatry, 2005, 58, 1–9

    PubMed  Google Scholar 

  23. Pilarsky R., Cowden syndrome: A critical review of the clinical literature, J. Genet. Couns., 2009, 18, 13–27

    Google Scholar 

  24. McBride K.L., Varga E.A., Pastore M.T., Prior T.W., Manickam K, Atkin J.F., et al., Confirmation of study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly, Biol. Autism Res., 2010, 3, 137–141

    Google Scholar 

  25. Tamguney T., Stokoe D., New insights into PTEN, J. Cell. Sci., 2007, 120, 4071–4079

    PubMed  CAS  Google Scholar 

  26. Nan X., Ng H.H., Johnson C.A., Laherty C.D., Turner B.M., Eisenman R.N., et al., Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex, Nature, 1998, 393, 386–389

    PubMed  CAS  Google Scholar 

  27. Muotri A.R., Marchetto M.C., Coufal N.G., Oefner R., Yeo G., Nakashima K, et al., L1 retrotransposition in neurons is modulated by MeCP2, Nature, 2010, 468, 443–446

    PubMed  CAS  Google Scholar 

  28. Skene P.J., Illingworth R.S., Webb S., Kerr A.R., James K.D., Turner D.J., et al., Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state, Mol. Cell, 2010, 37, 457–468

    PubMed  CAS  Google Scholar 

  29. Nelson W.J., Nusse R., Convergence of Wnt, β-catenin, and cadherin pathways, Science, 2004, 303, 1483–1487

    PubMed  CAS  Google Scholar 

  30. Persad S., Troussard A.A., McPhee T.R., Mulholland D.J., Dedhar S., Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation, J. Cell Biol., 2001, 153, 1161–1174

    PubMed  CAS  Google Scholar 

  31. Carney R.M., Wolpert C.M., Ravan S.A., Shahbazian M., Ashley-Koch A., Cuccaro M.L., et al., Identification of MeCP2 mutations in a series of females with autistic disorder, Pediatr. Neurol., 2003, 28, 205–211

    PubMed  Google Scholar 

  32. Samaco R.C., Nagarajan R.P., Braunschweig D., LaSalle J.M., Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders, Hum. Mol. Genet., 2004, 13, 629–639

    PubMed  CAS  Google Scholar 

  33. Steelman L.S., Abrams S.L., Whelan J., Bertrand F.E., Ludwig D.E., Bäsecke J., et al., Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia, Leukemia, 2008, 22, 686–707

    PubMed  CAS  Google Scholar 

  34. Kim D.H., Sarbassov D.D., Ali S.M., King J.E., Latek R.R., Erdjument-Bromage H., et al., mTOR interacts with raptor to form a nutrientsensitive complex that signals to the cell growth machinery, Cell, 2002, 110, 163–175

    PubMed  CAS  Google Scholar 

  35. Wiznitzer M., Autism and tuberous sclerosis, J. Child Neurol., 2004, 19, 675–679

    PubMed  Google Scholar 

  36. Ehninger D., De Vries P.J., Silva A.J., From mTOR to cognition: Molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis, J. Intellect. Disabil. Res., 2009, 53, 838–851

    PubMed  CAS  Google Scholar 

  37. Griffiths P.D., Gardner S.A., Smith M., Rittey C., Powell T., Hemimegalencephaly and focal megalencephaly in tuberous sclerosis complex, Am. J. Neuroradiol., 1998, 19, 1935–1938

    PubMed  CAS  Google Scholar 

  38. Christophe C., Sékhara T., Rypens F., Ziereisen F., Christiaens F., Dan B., MRI spectrum of cortical malformations in tuberous sclerosis complex, Brain Dev., 2000, 22, 487–493

    PubMed  CAS  Google Scholar 

  39. Way S.W., McKenna J. 3rd, Mietzsch U., Reith R.M., Wu H.C., Gambello M.J., Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse, Hum. Mol. Genet., 2009, 18, 1252–1265

    PubMed  CAS  Google Scholar 

  40. Bailey A., Luthert P., Dean A., Harding B., Janota I., Montgomery M., et al., A clinicopathological study of autism, Brain, 1998, 121, 889–905

    PubMed  Google Scholar 

  41. Wegiel J., Kuchna I., Nowicki K., Imaki H., Wegiel J., Marchi E., et al., The neuropathology of autism: Defects of neurogenesis and neuronal migration, and dysplastic changes, Acta Neuropathol., 2010, 119, 755–770

    PubMed  Google Scholar 

  42. Mak B.C., Takemaru K., Kenerson H.L., Moon R.T., Yeung R.S., The tuberin-hamartin complex negatively regulates beta-catenin signaling activity, J. Biol. Chem., 2003, 278, 5947–5951

    PubMed  CAS  Google Scholar 

  43. Daugherty R.L., Gottardi C.J., Phospho-regulation of β-catenin adhesion and signaling functions, Physiology, 2007, 22, 303–309

    PubMed  CAS  Google Scholar 

  44. Brown V., Jin P., Ceman S., Darnell J.C., O’Donnell W.T., Tenenbaum S.A., et al., Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome, Cell, 2001, 107, 477–487

    PubMed  CAS  Google Scholar 

  45. Luo Y., Shan G., Guo W., Smrt R.D., Johnson E.B., Li X., et al., Fragile X mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells, PLoS Genet., 2010, 6, e1000898

    PubMed  Google Scholar 

  46. Hagerman R.J., Fragile X syndrome, In: Bauman M.L., Kemper T.L. (Eds.), The neurobiology of autism, 2nd ed., The Johns Hopkins University Press, London, 2005, 251–264

    Google Scholar 

  47. Fatemi S.H., Folsom T.D., The role of fragile X mental retardation protein in major mental disorders, Neuropharmacology, 2011, 60, 1221–1226

    PubMed  CAS  Google Scholar 

  48. Zalfa F., Marcello G., Primerano B., Moro A., Di Penta A., Reis S., et al., The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses, Cell, 2003, 112, 317–327

    PubMed  CAS  Google Scholar 

  49. Castrén M., Tervonen T., Kärkkäinen V., Heinonen S., Castrén E., Larsson K., et al., Altered differentiation of neural stem cells in fragile X syndrome, Proc. Natl. Acad. Sci. U.S.A., 2005, 102, 17834–17839

    PubMed  Google Scholar 

  50. Tervonen T.A., Louhivuori V., Sun X., Hokkanen M.E., Kratochwil C.F., Zebryk P., et al., Aberrant differentiation of glutamatergic cells in neocortex of mouse model for fragile X syndrome, Neurobiol. Dis., 2009, 33, 250–259

    PubMed  CAS  Google Scholar 

  51. De Vries B.B.A., Mohkamsing S., Van den Ouweland A.M.W., Mol E., Gelsema K., Van Rijn M., et al., Screening for the fragile X syndrome among the mentally retarded: a clinical study, J. Med. Genet., 1999, 36, 467–470

    PubMed  Google Scholar 

  52. Chausovsky A., Bershadsky A.D., Borisy G.G., Cadherin-mediated regulation of microtubule dynamics, Nat. Cell Biol., 2000, 2, 797–804

    PubMed  CAS  Google Scholar 

  53. Reynolds A.B., Daniel J., McCrea P.D., Wheelock M.J., Wu J., Zhang Z., Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes, Mol. Cell Biol., 1994, 14, 8333–8342

    PubMed  CAS  Google Scholar 

  54. Bienz M., β-catenin: A pivot between cell adhesion and Wnt signalling, Curr. Biol., 2004, 15, R65

    Google Scholar 

  55. Ziegler S., Röhrs S., Tickenbrock L., Möröy T., Klein-Hitpass L., Vetter I.R., et al., Novel target genes of the Wnt pathway and statistical insights into Wnt target promoter regulation, FEBS J., 2005, 272, 1600–1615

    PubMed  CAS  Google Scholar 

  56. Gearhart J., Pashos E.E., Prasad M.K., Pluripotency redux—advances in stem-cell research, N. Engl. J. Med., 2007, 357, 1469–1472

    PubMed  CAS  Google Scholar 

  57. Cotterman R., Jin V.X., Krig S.R., Lemen J.M., Wey A., Farnham P.J., et al., N-Myc regulates a widespread euchromatic program in the human genome partially independent of its role as a classic transcription factor, Cancer Res., 2008, 68, 9654–9662

    PubMed  CAS  Google Scholar 

  58. Nusse R., A list of target genes of Wnt/beta-catenin signaling [online resource], Howard Hughes Medical Center, Stanford, 2009 [accessed 2011 Jan 28], http://www.stanford.edu/~rnusse/pathways/targets.html

    Google Scholar 

  59. Ding Q., Xia W., Liu J.C., Yang J.Y., Lee D.F., Xia J., et al., Erk associates with and primes GSK-3β for its inactivation resulting in upregulation of β-catenin, Mol. Cell, 2005, 19, 159–170

    PubMed  CAS  Google Scholar 

  60. Gherzi R., Trabucchi M., Ponassi M., Ruggiero T., Corte G., Moroni C., et al., The RNA-binding protein KSRP promotes decay of betacatenin mRNA and is inacitvated by PI3K-AKT signaling, PLoS Biol., 2006, 5, e5

    PubMed  Google Scholar 

  61. Bamji S.X., Shimazu K., Kimes N., Huelsken J., Birchmeier W., Lu B., et al., Role of beta-catenin in synaptic vesicle localization and presynaptic assembly, Neuron, 2003, 40, 719–731

    PubMed  CAS  Google Scholar 

  62. Kwon C.H., Luikart B.W., Powell C.M., Zhou J., Matheny S.A., Zhang W., et al., Pten regulates neuronal arborization and social interaction in mice, Neuron, 2006, 50, 377–388

    PubMed  CAS  Google Scholar 

  63. Wang Y., Greenwood J.S., Calcagnotto M.E., Kirsch H.E., Barbaro N.M., Baraban S.C., Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1, Ann. Neurol., 2007, 61, 139–152

    PubMed  CAS  Google Scholar 

  64. Nau H., Rating D., Koch S., Häuser I., Helge H., Valproic acid and its metabolites: Placental transfer, neonatal pharmacokinetics, transfer via mother’s milk and clinical status in neonates of epileptic mothers, J. Pharmacol. Exp. Ther., 1981, 219, 768–777

    PubMed  CAS  Google Scholar 

  65. DiLiberty J.H., Farndon P.A., Dennis N.R., Curry C.J., The fetal valproate syndrome, Am. J. Med. Genet., 1984, 19, 473–481

    Google Scholar 

  66. Christianson A.L., Chesler N., Kromberg J.G., Fetal valproate syndrome: Clinical and neuro-developmental features in two sibling pairs, Dev. Med. Child Neurol., 1994, 36, 361–369

    PubMed  CAS  Google Scholar 

  67. Moore S.J., Turnpenny P., Quinn A., Glover S., Lloyd D.J., Montgomery T., et al., A clinical study of 57 children with fetal anticonvulsant syndromes, J. Med. Genet., 2000, 37, 489–497

    PubMed  CAS  Google Scholar 

  68. Rasalam A.D., Hailey H., Williams J.H., Moore S.J., Turnpenny P.D., Lloyd D.J., et al., Characteristics of fetal anticonvulsant syndrome associated autistic disorder, Dev. Med. Child Neurol., 2005, 47, 551–555

    PubMed  CAS  Google Scholar 

  69. Markram H., Rinaldi T., Markram K.. The intense world syndrome—an alternative hypothesis for autism, Front. Neurosci., 2007, 1, 77–96

    PubMed  Google Scholar 

  70. Shimshoni J.A., Dalton E.C., Jenkins A., Eyal S., Ewan K., Williams R.S., et al., The effects of central nervous system-active valproic acid constitutional isomers, cyclopropyl analogs, and amide derivatives on neuronal growth cone behavior, Mol. Pharmacol., 2007, 71, 884–892

    PubMed  CAS  Google Scholar 

  71. Billin A.N., Thirlwell H., Ayer D.E., β-catenin-histone deacetylase interactions regulate the transition of LEF1 from a transcriptional repressor to an activator, Mol. Cell Biol., 2000, 20, 6882–6890

    PubMed  CAS  Google Scholar 

  72. Wiltse J., Mode of action: inhibition of histone deacetylase, altering WNT-dependent gene expression, and regulation of beta-catenin—developmental effects of valproic acid, Crit. Rev. Toxicol., 2005, 35, 727–738

    PubMed  CAS  Google Scholar 

  73. Wang Z., Xu L., Zhu X., Cui W., Sun Y., Nishijo H., et al., Demethylation of specitic Wnt/β-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure, Anat. Rec., 2010, 293, 1947–1953

    CAS  Google Scholar 

  74. Raballo R., Rhee J., Lyn-Cook R., Leckman J.F., Schwartz M.L., Vaccarino F.M., Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex., J. Neurosci., 2000, 20, 5012–5023

    PubMed  CAS  Google Scholar 

  75. Ryves J.W., Dalton E.C., Harwood A.J., Williams R.S., GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid, Bipolar Disord., 2005, 7, 260–265

    CAS  Google Scholar 

  76. Jope R.S., Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes, Trends Pharmacol. Sci., 2003, 24, 441–443

    PubMed  CAS  Google Scholar 

  77. Yuskaitis C.J., Mines M.A., King M.K., Sweatt J.D., Miller C.A., Jope R.S., Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome, Biochem. Pharmacol., 2010, 79, 632–646

    PubMed  CAS  Google Scholar 

  78. Hashimoto R., Senatorov V., Kanai H., Leeds P., Chuang D.M., Lithium stimulates progenitor proliferation in cultured brain neurons, Neuroscience, 2003, 117, 55–61

    PubMed  CAS  Google Scholar 

  79. Laeng P., Pitts R.L., Pemire A.L., Drabik C.E., Weiner A., Tang H., et al., The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells, J. Neurochem., 2004, 91, 238–251

    PubMed  CAS  Google Scholar 

  80. Vecsler M., Simon A.J., Amariglio N., Rechavi G., Gak E., MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro, Epigenetics, 2010, 5, 61–67

    PubMed  CAS  Google Scholar 

  81. Tropea D., Giacometti E, Wilson N.R., Beard C., McCurry C., Fu D.D., et al., Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice, Proc. Natl. Acad. Sci. U.S.A., 2009, 106, 2029–2034

    PubMed  CAS  Google Scholar 

  82. McCaffrey P., Deustch C.K., Macrocephaly and the control of brain growth in autistic disorders, Prog. Neurobiol., 2005, 77, 38–56

    Google Scholar 

  83. Croen L.A., Goines P., Braunschweig D., Yolkne R., Yoshida C.K., Grether J.K., et al., Brain-derived neurotrophic factor and autism: Maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) study, Autism Res., 2008, 1, 130–137

    PubMed  Google Scholar 

  84. Vaccarino F.M., Grigorenko E.L., Smith K.M., Stevens H.E., Regulation of cerebral cortical size and neuron number by fibroblast growth factors: Implications for autism, J. Autism Dev. Disord., 2009, 39, 511–520

    PubMed  Google Scholar 

  85. Baron-Cohen S., The extreme male brain theory of autism, Trends Cogn. Sci., 2002, 6, 248–254

    PubMed  Google Scholar 

  86. Knickmeyer R., Baron-Cohen S., Raggatt P., Taylor K., Hackett G., Fetal testosterone and empathy, Horm. Behav., 2006, 49, 282–292

    PubMed  CAS  Google Scholar 

  87. Knickmeyer R., Baron-Cohen S., Fane B.A., Wheelwright S., Mathews G.A., Conway G.S., et al., Androgens and autistic traits: a study of individuals with congenital adrenal hyperplasia, Horm. Behav., 2006, 50, 148–153

    PubMed  CAS  Google Scholar 

  88. Hague W.M., Adams J., Rodda C., Brook C.G., De Bruyn R., Grant D.B., et al., The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives, Clin. Endocrinol., 1990, 33, 501–510

    CAS  Google Scholar 

  89. Ingudomnukul E., Baron-Cohen S., Wheelwright S., Knickmeyer R., Elevated rates of testosterone-related disorders in women with autism spectrum conditions, Horm. Behav., 2007, 51, 597–604

    PubMed  CAS  Google Scholar 

  90. Shayya R., Chang R.J., Reproductive endocrinology of adolescent polycystic ovary syndrome, BJOG, 2010, 117, 150–155

    PubMed  CAS  Google Scholar 

  91. Yang F., Li X., Sharma M., Sasaki C.Y., Longo D.L., Lim B., et al., Linking beta-catenin to androgen-signaling pathway, J. Biol. Chem., 2002, 277, 11336–11344

    PubMed  CAS  Google Scholar 

  92. Pawlowski J.E., Ertel J.R., Allen M.P., Xu M., Butler C., Wilson E.M., et al., Liganded androgen receptor interaction with beta-catenin: Nuclear co-localization and modulation of transcriptional activity in neuronal cells, J. Biol. Chem., 2002, 277, 20702–20710

    PubMed  CAS  Google Scholar 

  93. Cullen D.A., Killick R., Leigh P.N., Gallo J.M., The effect of polyglutamine expansion in the human androgen receptor on its ability to suppress β-catenin-Tcf/Lef dependent transcription, Neurosci. Lett., 2004, 354, 54–58

    PubMed  CAS  Google Scholar 

  94. MacLusky N.J., Clark A.S., Naftolin F., Goldman-Rakic P.S., Estrogen formation in the mammalian brain: Possible role of aromatase in sexual differentiation of the hippocampus and neocortex, Steroids, 1987, 50, 459–474

    PubMed  CAS  Google Scholar 

  95. Lemmen J.G., Broekhof J.L.M., Kuiper G.G.J.M., Gustafsson J.Å., van der Saag P.T., van der Burg B., Expression of estrogen receptor alpha and beta during mouse embryogenesis, Mech. Dev., 1999, 81, 163–167

    PubMed  CAS  Google Scholar 

  96. Forlano P.M., Deitcher D.L., Myers D.A., Bass A.H., Anatomical distribution and cellular basis for high levels of aromatase activity in the brain of teleost fish: Aromatase enzyme and mRNA expression identify glia as source, J. Neurosci., 2001, 21, 8943–8955

    PubMed  CAS  Google Scholar 

  97. Wang L., Andersson S., Warner M., Gustafsson J.A., Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain, Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 703–708

    PubMed  CAS  Google Scholar 

  98. Pardridge W.M., Mietus L.J., Transport of steroid hormones through the rat blood-brain barrier, J. Clin. Invest., 1979, 64, 145–154

    PubMed  CAS  Google Scholar 

  99. Cardona-Gomez P., Perez M., Avila J., Garcia-Segura L.M., Wandosell F., Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus, Mol. Cell. Neurosci., 2004, 25, 363–373

    PubMed  CAS  Google Scholar 

  100. Perez-Martin M., Azcoitia I., Trejo J.L., Sierra A., Garcia-Segura L.M., An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat, Eur. J. Neurosci., 2003, 18, 923–930

    PubMed  Google Scholar 

  101. Homburg R., Pariente C., Lunenfeld B., Jacobs H.S., The role of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) in the pathogenesis of polycystic ovary syndrome, Hum. Reprod., 1992, 7, 1379–1383

    PubMed  CAS  Google Scholar 

  102. Kouzmenko A.P., Takeyama K., Ito S., Furatani T., Sawatsubashi S., Maki A., et al., Wnt/β-catenin and estrogen signaling converge in vivo, J. Biol. Chem., 2004, 279, 40255–40258

    PubMed  CAS  Google Scholar 

  103. Varea O., Garrido J.J., Dopazo A., Mendex P., Garcia-Segura L.M., Wandosell F., Estradiol activates beta-catenin dependent transcription in neurons, PLoS ONE, 2009, 4, e5153

    PubMed  Google Scholar 

  104. Simoncini T., Hafezi-Mghadam A., Brazil D.P., Ley K., Chin W.W., Liao J.K., Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase, Nature, 2000, 407, 538–541

    PubMed  CAS  Google Scholar 

  105. Kuiper G.G., Carlsson B., Grandien K., Enmark E., Häggblad J., Nilsson S., et al., Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta, Endocrinology, 1997, 138, 863–870

    PubMed  CAS  Google Scholar 

  106. Martin J.T., Sexual dimorphism in immune function: The role of prenatal exposure to androgens and estrogens, Eur. J. Pharmacol., 2000, 405, 251–261

    PubMed  CAS  Google Scholar 

  107. Warren R.P., Odell J.D., Warren W.L., Burger R.A., Maciulis A, Daniels W.W., et al., Brief report: Immunoglobulin A deficiency in a subset of autistic subjects, J. Autism Dev. Disord., 1997, 27, 187–192

    PubMed  CAS  Google Scholar 

  108. Gupta S., Aggarwal S., Rashanravan B., Lee T., Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism, J. Neuroimmunol., 1998, 85, 106–109

    PubMed  CAS  Google Scholar 

  109. Ashwood P., Van de Water J., Is autism an autoimmune disease? Autoimmun. Rev., 2004, 3, 557–562

    PubMed  CAS  Google Scholar 

  110. Li X., Chauhan A., Sheikh A.M., Patil S., Chauhan V., Li X.M., et al., Elevated immune response in the brain of autistic patients, J. Neuroimmunol., 2009, 207, 111–116

    PubMed  CAS  Google Scholar 

  111. Singh V.K., Phenotypic expression of autoimmune autistic disorder (AAD): A major subset of autism, Ann. Clin. Psychiatry, 2009, 21, 148–161

    PubMed  Google Scholar 

  112. Grether J.K., Croen L.A., Anderson M.C., Nelson K.B., Yolken R.H., Neonatally measured immunoglobulins and risk of autism, Autism Res., 2010, 3, 323–332

    PubMed  Google Scholar 

  113. Angelidou A., Alysandratos K.D., Asadi S., Zhang B., Francis K., Vasiadi M., et al., Brief report: “Allergic symptoms” in children with autism spectrum disorders. More than meets the eye? J. Autism Dev. Disord., (in press), DOI: 10.1007/s10803-010-1171-z

  114. Chess S., Fernandez P., Korn S., Behavioral consequences of congenital rubella, J. Pediatr., 1978, 93, 699–703

    PubMed  CAS  Google Scholar 

  115. Taga T., Fukuda S., Role of IL-6 in the neural stem cell differentiation, Clin. Rev. Allergy Immunol., 2005, 28, 249–256

    PubMed  CAS  Google Scholar 

  116. Carpentier P.A., Palmer T.D., Immune influence on adult neural stem cell regulation and function, Neuron, 2009, 64, 79–92

    PubMed  CAS  Google Scholar 

  117. Wolf S.A., Steiner B., Wengner A., Lipp M., Kammertoens T., Kempermann G., Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus, FASEB J., 2009, 23, 3121–3128

    PubMed  CAS  Google Scholar 

  118. Sarkar P., Bergman K., O’Connor T.G., Glover V., Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: Possible implications for foetal programming, J. Neuroendocrinol., 2008, 20, 489–496

    PubMed  CAS  Google Scholar 

  119. Pascual R., Ebner D., Araneda R., Urqueta M.J., Bustamante C., Maternal stress induces long-lasting Purkinje cell developmental impairments in mouse offspring, Eur. J. Pediatr., 2010, 169, 1517–1522

    PubMed  Google Scholar 

  120. You J.J., Alter D.A., Stukel T.A., McDonald S.D., Laupacis A., Liu Y., et al., Proliferation of prenatal ultrasound, Can. Med. Assoc. J., 2010, 182, 143–151

    Google Scholar 

  121. Miller M.W., Brayman A.A., Abramowicz J.S., Obstetric ultrasonography: a biophysical consideration of patient safety-the “rules” have changed, Am. J. Obstet. Gynecol., 1998, 179, 241–254

    PubMed  CAS  Google Scholar 

  122. Sheiner E., Shoham-Vardi I., Abramowicz J.S., What do clinical users know regarding safety of ultrasound during pregnancy? J. Ultrasound Med., 2007, 26, 319–325

    PubMed  Google Scholar 

  123. Williams E.L., Casanova M.F., Potential teratogenic effects of ultrasound on corticogenesis: Implications for autism, Med. Hypotheses, 2010, 75, 53–58

    PubMed  CAS  Google Scholar 

  124. Dyson M., Franks C., Suckling J., Stimulation of healing of varicose ulcers by ultrasound, Ultrasonics, 1976, 14, 232–236

    PubMed  CAS  Google Scholar 

  125. Duarte L.R., The stimulation of bone growth by ultrasound, Arch. Orthop. Trauma Surg., 1983, 101, 153–159

    PubMed  CAS  Google Scholar 

  126. Ang E.S. Jr, Gluncic V., Duque A., Schafer M.E., Rakic P., Prenatal exposure to ultrasound waves impacts neuronal migration in mice, Proc. Natl. Acad. Sci. U.S.A., 2006, 103, 12903–12910

    PubMed  CAS  Google Scholar 

  127. Sikov M.R., Effects of ultrasound on development. Part 2: Studies in mammalian species and overview, J. Ultrasound Med., 1986, 5, 651–661

    PubMed  CAS  Google Scholar 

  128. Olkku A., Leskinen J.J., Lammi M.J., Hynynen K., Mahonen A., Ultrasound-induced activation of Wnt signaling in human MG-63 osteoblastic cells, Bone, 2010, 47, 320–330

    PubMed  CAS  Google Scholar 

  129. Takeuchi R., Ryo A., Komitsu N., Mikuni-Takagaki Y., Fukui A., Takagi Y., et al., Low-intensity pulsed ultrasound activates the phosophatidylinositol 3 kinase/Akt pathway and stimulates the growth of chondrocytes in three-dimensional cultures: A basic science study, Arthritis Res. Ther., 2008, 10, R77

    PubMed  Google Scholar 

  130. Mitragotri S., Blankschtein D., Langer R., Ultrasound-mediated transdermal protein delivery, Science, 1995, 269, 850–853

    PubMed  CAS  Google Scholar 

  131. Van Wamel A., Bouakaz A., Versluis M., De Jong N., Micromanipulation of endothelial cells: Ultrasound-microbubble-cell interaction, Ultrasound Med. Biol., 2004, 30, 1255–1258

    PubMed  Google Scholar 

  132. VanBavel E., Effects of shear stress on endothelial cells: Possible relevance for ultrasound applications, Prog. Biophys. Mol. Biol., 2007, 93, 374–383

    PubMed  CAS  Google Scholar 

  133. Colombo A., Hall P., Nakamura S., Almagor Y., Maiello L., Martini G., et al., Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance, Circulation, 1995, 91, 1676–1688

    PubMed  CAS  Google Scholar 

  134. Rioufol G., Finet G., Ginon I., André-Fouët X., Rossi R., Vialle E., et al., Multiple atherosclerotic plaque rupture in acute coronary syndrome: A three-vessel intravascular ultrasound study, Circulation, 2002, 106, 804–808

    PubMed  CAS  Google Scholar 

  135. Yamamoto K., Takahashi T., Asahara T., Ohura N., Sokabe T., Kamiya A., et al., Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress, J. Appl. Physiol., 2003, 95, 2081–2088

    PubMed  Google Scholar 

  136. Reher P., Doan N., Bradnock B., Meghji S., Harris M., Effect of ultrasound on the production of IL-8, basic FGF and VEGF, Cytokine, 1999, 11, 416–423

    CAS  Google Scholar 

  137. Reher P., Harris M., Whiteman M., Hai H.K., Meghji S., Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts, Bone, 2002, 31, 236–241

    PubMed  CAS  Google Scholar 

  138. Raab S., Plate K.H., Different networks, common growth factors: Shared growth factors and receptors of the vascular and the nervous system, Acta Neuropathol., 2007, 113, 607–626

    PubMed  CAS  Google Scholar 

  139. Shen Q., Goderie S.K., Jin L., Karanth N., Sun Y., Abramova N., et al., Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells, Science, 2004, 304, 1338–1340

    PubMed  CAS  Google Scholar 

  140. Sun J., Zhou W., Ma D., Yang Y., Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling, Dev. Dyn., 2010, 239, 2345–2353

    PubMed  CAS  Google Scholar 

  141. Shen Q., Wang Y., Kokovay E., Lin G., Chuang S.M., Goderie S.K., et al., Adult SVZ stem cells lie in a vascular niche: A quantitative analysis of niche cell-cell interactions, Cell Stem Cell, 2008, 3, 289–300

    PubMed  CAS  Google Scholar 

  142. Ye H., Liu J., Wu J.Y., Cell adhesion molecules and their involvement in autism spectrum disorder, Neurosignals, 2011, 18, 62–71

    Google Scholar 

  143. Jamain S., Quach H., Betancur C., Råstam M., Colineaux C., Gillberg I.C., et al., Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat. Genet., 2003, 34, 27–29

    PubMed  CAS  Google Scholar 

  144. Laumonnier F., Bonnet-Brilhault F., Gomot M., Blanc R., David A., Moizard M.P., et al., X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family, Am. J. Hum. Genet., 2004, 74, 552–557

    PubMed  CAS  Google Scholar 

  145. Feng J., Schroer R., Yan J., Song W., Yang C., Bockholt A, et al., High frequency of neurexin 1beta signal peptide structural variants in patients with autism, Neurosci. Lett., 2006, 409, 10–13

    PubMed  CAS  Google Scholar 

  146. Kim H.G., Kishikawa S., Higgins A.W., Seong I.S., Donovan D.J., Shen Y., et al., Disruption of neurexin 1 associated with autism spectrum disorder, Am. J. Hum. Genet., 2008, 82, 199–207

    PubMed  CAS  Google Scholar 

  147. Chen S.X., Tari P.K., She K., Haas K., Neurexin-neuroligin cell adhesion complexes contribute to synaptotropic dendritogenesis via growth stabilization mechanisms in vivo, Neuron, 2010, 67, 967–983

    PubMed  CAS  Google Scholar 

  148. Chih B., Engelman H., Scheiffele P., Control of excitatory and inhibitory synapse formation by neuroligins, Science, 2005, 307, 1324–1328

    PubMed  CAS  Google Scholar 

  149. Budreck E.C., Scheiffele P., Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses, Eur. J. Neurosci., 2007, 26, 1738–1748

    PubMed  Google Scholar 

  150. Hirao K., Hata Y., Ide N., Takeuchi M., Irie M., Yao I., et al., A novel multiple PDZ domain-containing molecule interacting with N-methyl-D-aspartate receptors and neuronal cell adhesion proteins, J. Biol. Chem., 1998, 273, 21105–21110

    PubMed  CAS  Google Scholar 

  151. Barrow S.L., Constable J.R., Clark E., El-Sabeawy F., McAllister A.K., Washbourne P., Neuroligin1: A cell adhesion molecule that recruits PSD-95 and NMDA receptors by distinct mechanisms during synaptogenesis, Neural Dev., 2009, 4, 17

    PubMed  Google Scholar 

  152. Murase S., Mosser E., Schuman E.M., Depolarization drives betacatenin into neuronal spines promoting changes in synaptic structure and function, Neuron, 2002, 35, 91–105

    PubMed  CAS  Google Scholar 

  153. Stan A., Pielarski K.N., Brigadski T., Wittenmayer N., Fedorchenko O., Gohla A., et al., Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation, Proc. Natl. Acad. Sci. U.S.A., 2010, 107, 11116–11121

    PubMed  CAS  Google Scholar 

  154. Yu X., Malenka R.C., β-catenin is critical for dendritic morphogenesis, Nat. Neurosci., 2003, 6, 1169–1177

    PubMed  CAS  Google Scholar 

  155. Abe K., Takeichi M., NMDA-receptor activation induces calpainmediated β-catenin cleavages for triggering gene expression, Neuron, 2007, 53, 387–397

    PubMed  CAS  Google Scholar 

  156. Derksen M.J., Ward N.L., Hartle K.D., Ivanco T.L., MAP2 and synaptophysin protein expression following motor learning suggests dynamic regulation and distinct alterations coinciding with synaptogenesis, Neurobiol. Learn. Mem., 2007, 87, 404–415

    PubMed  CAS  Google Scholar 

  157. Antar L.N., Afroz R., Dictenberg J.B., Carroll R.C., Bassell G.J., Metabotropic glutamate receptor activation regulates fragile X mental retardation protein and Fmr1 mRNA localization differentially in dendrites and at synapses, J. Neurosci., 2004, 24, 2648–2655

    PubMed  CAS  Google Scholar 

  158. Wang H., Dictenberg J.B., Ku L., Li W., Bassell G.J., Feng Y., Dynamic association of the fragile X mental retardation protein as a messenger ribonucleoprotein between microtubules and polyribosomes, Mol. Biol. Cell, 2008, 19, 105–114

    PubMed  CAS  Google Scholar 

  159. Nimchinsky E.A., Oberlander A.M., Svoboda K., Abnormal development of dendritic spines in FMR1 knock-out mice, J. Neurosci., 2001, 21, 5139–5146

    PubMed  CAS  Google Scholar 

  160. Allin E.F., Evolution of the mammalian middle ear, J. Morphol., 1975, 147, 403–437

    PubMed  CAS  Google Scholar 

  161. Sakarya O., Armstrong K.A., Adamska M., Adamski M., Wang I.F., Tidor B., et al., A post-synaptic scaffold at the origin of the animal kingdom, PLoS ONE, 2007, 2, e506

    PubMed  Google Scholar 

  162. Nickel M., Evolutionary emergence of synaptic nervous systems: What can we learn from the non-synaptic, nerveless Porifera? Invertebr. Biol., 2010, 129, 1–16

    Google Scholar 

  163. Pinto D., Pagnamenta A.T., Klei L., Anney R., Merico D., Regan R., et al., Functional impact of global rare copy number variation in autism spectrum disorders, Nature, 2010, 466, 368–372

    PubMed  CAS  Google Scholar 

  164. Kolkova K., Novitskaya V., Pedersen N., Berezin V., Bock E., Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway, J. Neurosci., 2000, 20, 2238–2246

    PubMed  CAS  Google Scholar 

  165. Chang L., Karin M., Mammalian MAP kinase signalling cascades, Nature, 2001, 410, 37–40

    PubMed  CAS  Google Scholar 

  166. Laws S.C., Carey S.A., Ferrell J.M., Bodman G.J., Cooper R.L., Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats, Toxicol. Sci., 2000, 54, 154–167

    PubMed  CAS  Google Scholar 

  167. Hertz-Picciotto I., Delwiche L., The rise in autism and the role of age at diagnosis, Epidemiology, 2009, 20, 84–90

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, 40202, USA

    Emily L. Williams

  2. Department of Psychiatry and Behavioral Sciences, University of Louisville, Louisville, KY, 40202, USA

    Manuel F. Casanova

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  1. Emily L. Williams
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  2. Manuel F. Casanova
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Correspondence to Emily L. Williams.

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Williams, E.L., Casanova, M.F. Above genetics: Lessons from cerebral development in autism. Translat.Neurosci. 2, 106–120 (2011). https://doi.org/10.2478/s13380-011-0016-3

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Keywords

  • Beta catenin
  • Minicolumns
  • Neural stem cells
  • Rett syndrome
  • Fragile X syndrome
  • Tuberous sclerosis
  • Valproic acid
  • Pten phosphohydrolase
  • Ultrasonography
  • Cell adhesion molecules
  • neuronal