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Dysregulation of Neurite Outgrowth and Cell Migration in Autism and Other Neurodevelopmental Disorders

  • Smrithi Prem
  • James H. Millonig
  • Emanuel DiCicco-BloomEmail author
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)

Abstract

Despite decades of study, elucidation of the underlying etiology of complex developmental disorders such as autism spectrum disorder (ASD), schizophrenia (SCZ), intellectual disability (ID), and bipolar disorder (BPD) has been hampered by the inability to study human neurons, the heterogeneity of these disorders, and the relevance of animal model systems. Moreover, a majority of these developmental disorders have multifactorial or idiopathic (unknown) causes making them difficult to model using traditional methods of genetic alteration. Examination of the brains of individuals with ASD and other developmental disorders in both post-mortem and MRI studies shows defects that are suggestive of dysregulation of embryonic and early postnatal development. For ASD, more recent genetic studies have also suggested that risk genes largely converge upon the developing human cerebral cortex between weeks 8 and 24 in utero. Yet, an overwhelming majority of studies in autism rodent models have focused on postnatal development or adult synaptic transmission defects in autism related circuits. Thus, studies looking at early developmental processes such as proliferation, cell migration, and early differentiation, which are essential to build the brain, are largely lacking. Yet, interestingly, a few studies that did assess early neurodevelopment found that alterations in brain structure and function associated with neurodevelopmental disorders (NDDs) begin as early as the initial formation and patterning of the neural tube. By the early to mid-2000s, the derivation of human embryonic stem cells (hESCs) and later induced pluripotent stem cells (iPSCs) allowed us to study living human neural cells in culture for the first time. Specifically, iPSCs gave us the unprecedented ability to study cells derived from individuals with idiopathic disorders. Studies indicate that iPSC-derived neural cells, whether precursors or “matured” neurons, largely resemble cortical cells of embryonic humans from weeks 8 to 24. Thus, these cells are an excellent model to study early human neurodevelopment, particularly in the context of genetically complex diseases. Indeed, since 2011, numerous studies have assessed developmental phenotypes in neurons derived from individuals with both genetic and idiopathic forms of ASD and other NDDs. However, while iPSC-derived neurons are fetal in nature, they are post-mitotic and thus cannot be used to study developmental processes that occur before terminal differentiation. Moreover, it is important to note that during the 8–24-week window of human neurodevelopment, neural precursor cells are actively undergoing proliferation, migration, and early differentiation to form the basic cytoarchitecture of the brain. Thus, by studying NPCs specifically, we could gain insight into how early neurodevelopmental processes contribute to the pathogenesis of NDDs. Indeed, a few studies have explored NPC phenotypes in NDDs and have uncovered dysregulations in cell proliferation. Yet, few studies have explored migration and early differentiation phenotypes of NPCs in NDDs. In this chapter, we will discuss cell migration and neurite outgrowth and the role of these processes in neurodevelopment and NDDs. We will begin by reviewing the processes that are important in early neurodevelopment and early cortical development. We will then delve into the roles of neurite outgrowth and cell migration in the formation of the brain and how errors in these processes affect brain development. We also provide review of a few key molecules that are involved in the regulation of neurite outgrowth and migration while discussing how dysregulations in these molecules can lead to abnormalities in brain structure and function thereby highlighting their contribution to pathogenesis of NDDs. Then we will discuss whether neurite outgrowth, migration, and the molecules that regulate these processes are associated with ASD. Lastly, we will review the utility of iPSCs in modeling NDDs and discuss future goals for the study of NDDs using this technology.

Keywords

Neurodevelopmental disorders Autism Neurite outgrowth Cell migration Early neurodevelopment iPSCs NPCs 

Notes

Acknowledgments This work was supported by the New Jersey Governor’s Council for Medical Research and Treatment of Autism (CAUT13APS010; CAUT14APL031; CAUT15APL041, CAUT19APL014) and Nancy Lurie Marks Family Foundation for Dr. DiCicco-Bloom and Dr. Millonig; NJ Health Foundation (PC 63-19) for Dr. Millonig; Mindworks Charitable Lead Trust, and the Jewish Community Foundation of Greater MetroWest for Dr. DiCicco-Bloom; and the Rutgers Graduate School of Biomedical Sciences for Dr. Prem and Dr. DiCicco-Bloom.

References

  1. 1.
    Kandel, E. R., Schwartz, J. H., Jessell, T. M., Siegelbaum, S. A., & Hudspeth, A. J. (2000). Principles of neural science. New York: McGraw-Hill.Google Scholar
  2. 2.
    DiCicco-Bloom, E., & Obiorah, M. (2017). Neural development and neurogenesis. In B. J. Saddock, V. Saddock, & P. Ruiz (Eds.), Kaplan & Sadock’s comprehensive textbook of psychiatry. 1 (10th ed., pp. 39–60). Philadelphia: Wolters Kluwer.Google Scholar
  3. 3.
    Clancy, B., Finlay, B. L., Darlington, R. B., & Anand, K. J. (2007). Extrapolating brain development from experimental species to humans. Neurotoxicology, 28(5), 931–937.PubMedGoogle Scholar
  4. 4.
    Clancy, B., Darlington, R. B., & Finlay, B. L. (2001). Translating developmental time across mammalian species. Neuroscience, 105(1), 7–17.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Molnar, Z., Metin, C., Stoykova, A., Tarabykin, V., Price, D. J., Francis, F., et al. (2006). Comparative aspects of cerebral cortical development. The European Journal of Neuroscience, 23(4), 921–934.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Shipp, S. (2007). Structure and function of the cerebral cortex. Current Biology, 17(12), R443–R4R9.PubMedGoogle Scholar
  7. 7.
    Martynoga, B., Drechsel, D., & Guillemot, F. (2012). Molecular control of neurogenesis: A view from the mammalian cerebral cortex. Cold Spring Harbor Perspectives in Biology, 4(10), a008359.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Urban, N., & Guillemot, F. (2014). Neurogenesis in the embryonic and adult brain: Same regulators, different roles. Frontiers in Cellular Neuroscience, 8, 396.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Sansom, S. N., Griffiths, D. S., Faedo, A., Kleinjan, D. J., Ruan, Y., Smith, J., et al. (2009). The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genetics, 5(6), e1000511.PubMedPubMedCentralGoogle Scholar
  10. 10.
    McConnell, S. K. (1995). Constructing the cerebral cortex: Neurogenesis and fate determination. Neuron, 15(4), 761–768.PubMedGoogle Scholar
  11. 11.
    Hansen, A. H., Duellberg, C., Mieck, C., Loose, M., & Hippenmeyer, S. (2017). Cell polarity in cerebral cortex development-cellular architecture shaped by biochemical networks. Frontiers in Cellular Neuroscience, 11, 176.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Pressler, R., & Auvin, S. (2013). Comparison of brain maturation among species: An example in translational research suggesting the possible use of bumetanide in newborn. Frontiers in Neurology, 4, 36.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Stiles, J., & Jernigan, T. L. (2010). The basics of brain development. Neuropsychology Review, 20(4), 327–348.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Rubenstein, J. L. R. (2011). Development of the cerebral cortex: Implications for neurodevelopmental disorders. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 52(4), 339–355.Google Scholar
  15. 15.
    Nicholas, C. R., Chen, J., Tang, Y., Southwell, D. G., Chalmers, N., Vogt, D., et al. (2013). Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell, 12(5), 573–586.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Hansen, D. V., Lui, J. H., Parker, P. R., & Kriegstein, A. R. (2010). Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature, 464(7288), 554–561.PubMedPubMedCentralGoogle Scholar
  17. 17.
    LaMonica, B. E., Lui, J. H., Wang, X., & Kriegstein, A. R. (2012). OSVZ progenitors in the human cortex: An updated perspective on neurodevelopmental disease. Current Opinion in Neurobiology, 22(5), 747–753.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Vitalis, T., & Verney, C. (2017). Sculpting cerebral cortex with serotonin in rodent and primate. In K. F. Shad (Ed.), Serotonin - A chemical messenger between all types of living cells. Rijeka: InTech. p. Ch. 05.Google Scholar
  19. 19.
    Nadarajah, B., Alifragis, P., Wong, R. O., & Parnavelas, J. G. (2003). Neuronal migration in the developing cerebral cortex: Observations based on real-time imaging. Cerebral Cortex, 13(6), 607–611.PubMedGoogle Scholar
  20. 20.
    Stanco, A., & Anton, E. S. (2013). Chapter 17 - Radial migration of neurons in the cerebral cortex. In J. L. R. Rubenstein & P. Rakic (Eds.), Cellular migration and formation of neuronal connections (pp. 317–330). Oxford: Academic Press.Google Scholar
  21. 21.
    Sekine K, Tabata H, Nakajima K. Chapter 12 - Cell polarity and initiation of migration- Rubenstein, John L.R. In: Rakic P, editor. Cellular migration and formation of neuronal connections. Oxford, Academic Press; 2013. p. 231–244.Google Scholar
  22. 22.
    Noctor, S. C., Cunningham, C. L., & Kriegstein, A. R. (2013). Chapter 16 - Radial migration in the developing cerebral cortex. In J. L. R. Rubenstein & P. Rakic (Eds.), Cellular migration and formation of neuronal connections (pp. 299–316). Oxford: Academic Press.Google Scholar
  23. 23.
    Reiner, O., Karzbrun, E., Kshirsagar, A., & Kaibuchi, K. (2016). Regulation of neuronal migration, an emerging topic in autism spectrum disorders. Journal of Neurochemistry, 136(3), 440–456.PubMedGoogle Scholar
  24. 24.
    Tissir, F., & Goffinet, A. M. (2003). Reelin and brain development. Nature Reviews. Neuroscience, 4(6), 496–505.PubMedGoogle Scholar
  25. 25.
    Jossin, Y., Bar, I., Ignatova, N., Tissir, F., De Rouvroit, C. L., & Goffinet, A. M. (2003). The reelin signaling pathway: Some recent developments. Cerebral Cortex, 13(6), 627–633.PubMedGoogle Scholar
  26. 26.
    D'Arcangelo, G. (2014). Reelin in the years: Controlling neuronal migration and maturation in the mammalian brain. Advances in Neuroscience, 2014, 19.Google Scholar
  27. 27.
    Boyle, M. P., Bernard, A., Thompson, C. L., Ng, L., Boe, A., Mortrud, M., et al. (2011). Cell-type-specific consequences of reelin deficiency in the mouse neocortex, hippocampus, and amygdala. The Journal of Comparative Neurology, 519(11), 2061–2089.PubMedGoogle Scholar
  28. 28.
    Kawauchi, T., & Hoshino, M. (2008). Molecular pathways regulating cytoskeletal organization and morphological changes in migrating neurons. Developmental Neuroscience, 30(1–3), 36–46.PubMedGoogle Scholar
  29. 29.
    Bar, I., Tissir, F., Lambert de Rouvroit, C., De Backer, O., & Goffinet, A. M. (2003). The gene encoding disabled-1 (DAB1), the intracellular adaptor of the reelin pathway, reveals unusual complexity in human and mouse. The Journal of Biological Chemistry, 278(8), 5802–5812.PubMedGoogle Scholar
  30. 30.
    Hevner, R. F., Shi, L., Justice, N., Hsueh, Y., Sheng, M., Smiga, S., et al. (2001). Tbr1 regulates differentiation of the preplate and layer 6. Neuron, 29(2), 353–366.PubMedGoogle Scholar
  31. 31.
    Gilmore, E. C., & Herrup, K. (2000). Cortical development: Receiving reelin. Current Biology, 10(4), R162–R166.PubMedGoogle Scholar
  32. 32.
    O'Kusky, J., & Ye, P. (2012). Neurodevelopmental effects of insulin-like growth factor signaling. Frontiers in Neuroendocrinology, 33(3), 230–251.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J., & Efstratiadis, A. (1993). Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell, 75(1), 59–72.PubMedGoogle Scholar
  34. 34.
    Nieto Guil, A. F., Oksdath, M., Weiss, L. A., Grassi, D. J., Sosa, L. J., Nieto, M., et al. (2017). IGF-1 receptor regulates dynamic changes in neuronal polarity during cerebral cortical migration. Scientific Reports, 7(1), 7703.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Gennarini, G., & Furley, A. (2017). Cell adhesion molecules in neural development and disease. Molecular and Cellular Neurosciences, 81, 1–3.PubMedGoogle Scholar
  36. 36.
    Miyamoto, Y., Sakane, F., & Hashimoto, K. (2015). N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development. Cell Adhesion & Migration, 9(3), 183–192.Google Scholar
  37. 37.
    Kadowaki, M., Nakamura, S., Machon, O., Krauss, S., Radice, G. L., & Takeichi, M. (2007). N-cadherin mediates cortical organization in the mouse brain. Developmental Biology, 304(1), 22–33.PubMedGoogle Scholar
  38. 38.
    Shikanai, M., Nakajima, K., & Kawauchi, T. (2011). N-cadherin regulates radial glial fiber-dependent migration of cortical locomoting neurons. Communicative & Integrative Biology, 4(3), 326–330.Google Scholar
  39. 39.
    Takeichi, M., Inuzuka, H., Shimamura, K., Fujimori, T., & Nagafuchi, A. (1990). Cadherin subclasses: Differential expression and their roles in neural morphogenesis. Cold Spring Harbor Symposia on Quantitative Biology, 55, 319–325.PubMedGoogle Scholar
  40. 40.
    Suzuki, S. C., & Takeichi, M. (2008). Cadherins in neuronal morphogenesis and function. Development, Growth & Differentiation, 50(Suppl 1), S119–S130.Google Scholar
  41. 41.
    Bixby, J. L., Grunwald, G. B., & Bookman, R. J. (1994). Ca2+ influx and neurite growth in response to purified N-cadherin and laminin. The Journal of Cell Biology, 127(5), 1461–1475.PubMedGoogle Scholar
  42. 42.
    Gartner, A., Fornasiero, E. F., Munck, S., Vennekens, K., Seuntjens, E., Huttner, W. B., et al. (2012). N-cadherin specifies first asymmetry in developing neurons. The EMBO Journal, 31(8), 1893–1903.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Gartner, A., Fornasiero, E. F., & Dotti, C. G. (2012). N-cadherin: A new player in neuronal polarity. Cell Cycle, 11(12), 2223–2224.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Gartner, A., Fornasiero, E. F., & Dotti, C. G. (2015). Cadherins as regulators of neuronal polarity. Cell Adhesion & Migration, 9(3), 175–182.Google Scholar
  45. 45.
    Nelson, W. J., & Nusse, R. (2004). Convergence of Wnt, beta-catenin, and cadherin pathways. Science, 303(5663), 1483–1487.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Chenn, A., & Walsh, C. A. (2003). Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cerebral Cortex, 13(6), 599–606.PubMedGoogle Scholar
  47. 47.
    Arikkath, J., & Reichardt, L. F. (2008). Cadherins and catenins at synapses: Roles in synaptogenesis and synaptic plasticity. Trends in Neurosciences, 31(9), 487–494.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Compagnucci, C., Piemonte, F., Sferra, A., Piermarini, E., & Bertini, E. (2016). The cytoskeletal arrangements necessary to neurogenesis. Oncotarget, 7(15), 19414–19429.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Cearns, M. D., Escuin, S., Alexandre, P., Greene, N. D., & Copp, A. J. (2016). Microtubules, polarity and vertebrate neural tube morphogenesis. Journal of Anatomy, 229(1), 63–74.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Messier, P. E. (1978). Microtubules, interkinetic nuclear migration and neurulation. Experientia, 34(3), 289–296.PubMedGoogle Scholar
  51. 51.
    Breuss, M. W., Leca, I., Gstrein, T., Hansen, A. H., & Keays, D. A. (2017). Tubulins and brain development - the origins of functional specification. Molecular and Cellular Neurosciences, 84, 58–67.PubMedGoogle Scholar
  52. 52.
    Belvindrah, R., Natarajan, K., Shabajee, P., Bruel-Jungerman, E., Bernard, J., Goutierre, M., et al. (2017). Mutation of the alpha-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration. The Journal of Cell Biology, 216(8), 2443–2461.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Aiken, J., Moore, J. K., & Bates, E. A. (2019). TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. Human Molecular Genetics, 28, 1227.PubMedGoogle Scholar
  54. 54.
    Bamba, Y., Shofuda, T., Kato, M., Pooh, R. K., Tateishi, Y., Takanashi, J., et al. (2016). In vitro characterization of neurite extension using induced pluripotent stem cells derived from lissencephaly patients with TUBA1A missense mutations. Molecular Brain, 9(1), 70.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Reiner, O. (2013). LIS1 and DCX: Implications for brain development and human disease in relation to microtubules. Scientifica, 2013, 393975.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Reiner, O., & Sapir, T. (2013). LIS1 functions in normal development and disease. Current Opinion in Neurobiology, 23(6), 951–956.PubMedGoogle Scholar
  57. 57.
    Ayanlaja, A. A., Xiong, Y., Gao, Y., Ji, G., Tang, C., Abdikani Abdullah, Z., et al. (2017). Distinct features of doublecortin as a marker of neuronal migration and its implications in cancer cell mobility. Frontiers in Molecular Neuroscience, 10, 199.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Gleeson, J. G., Lin, P. T., Flanagan, L. A., & Walsh, C. A. (1999). Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron, 23(2), 257–271.PubMedGoogle Scholar
  59. 59.
    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. Nature Neuroscience, 6(12), 1277–1283.PubMedGoogle Scholar
  60. 60.
    Allen, K. M., & Walsh, C. A. (1999). Genes that regulate neuronal migration in the cerebral cortex. Epilepsy Research, 36(2–3), 143–154.PubMedGoogle Scholar
  61. 61.
    Filipovic, R., Santhosh Kumar, S., Fiondella, C., & Loturco, J. (2012). Increasing doublecortin expression promotes migration of human embryonic stem cell-derived neurons. Stem Cells, 30(9), 1852–1862.PubMedPubMedCentralGoogle Scholar
  62. 62.
    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. The Journal of Cell Biology, 170(6), 935–945.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Takei, Y., Teng, J., Harada, A., & Hirokawa, N. (2000). Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. The Journal of Cell Biology, 150(5), 989–1000.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Teng, J., Takei, Y., Harada, A., Nakata, T., Chen, J., & Hirokawa, N. (2001). Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. The Journal of Cell Biology, 155(1), 65–76.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Gallo, G. (2013). Mechanisms underlying the initiation and dynamics of neuronal filopodia: From neurite formation to synaptogenesis. International Review of Cell and Molecular Biology, 301, 95–156.PubMedGoogle Scholar
  66. 66.
    Lafont, F., Rouget, M., Rousselet, A., Valenza, C., & Prochiantz, A. (1993). Specific responses of axons and dendrites to cytoskeleton perturbations: An in vitro study. Journal of Cell Science, 104(Pt 2), 433–443.PubMedGoogle Scholar
  67. 67.
    Bentley, D., & Toroian-Raymond, A. (1986). Disoriented pathfinding by pioneer neurone growth cones deprived of filopodia by cytochalasin treatment. Nature, 323(6090), 712–715.PubMedGoogle Scholar
  68. 68.
    Azzarelli, R., Kerloch, T., & Pacary, E. (2014). Regulation of cerebral cortex development by Rho GTPases: Insights from in vivo studies. Frontiers in Cellular Neuroscience, 8, 445.PubMedGoogle Scholar
  69. 69.
    Kawauchi, T., Chihama, K., Nabeshima, Y., & Hoshino, M. (2003). The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. The EMBO Journal, 22(16), 4190–4201.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Konno, D., Yoshimura, S., Hori, K., Maruoka, H., & Sobue, K. (2005). Involvement of the phosphatidylinositol 3-kinase/rac1 and cdc42 pathways in radial migration of cortical neurons. The Journal of Biological Chemistry, 280(6), 5082–5088.PubMedGoogle Scholar
  71. 71.
    Heng, J. I., Nguyen, L., Castro, D. S., Zimmer, C., Wildner, H., Armant, O., et al. (2008). Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature, 455(7209), 114–118.PubMedGoogle Scholar
  72. 72.
    Pacary, E., Heng, J., Azzarelli, R., Riou, P., Castro, D., Lebel-Potter, M., et al. (2011). Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling. Neuron, 69(6), 1069–1084.PubMedGoogle Scholar
  73. 73.
    Chen, L., Liao, G., Waclaw, R. R., Burns, K. A., Linquist, D., Campbell, K., et al. (2007). Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. The Journal of Neuroscience, 27(14), 3884–3893.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Yang, T., Sun, Y., Zhang, F., Zhu, Y., Shi, L., Li, H., et al. (2012). POSH localizes activated Rac1 to control the formation of cytoplasmic dilation of the leading process and neuronal migration. Cell Reports, 2(3), 640–651.PubMedGoogle Scholar
  75. 75.
    Kassai, H., Terashima, T., Fukaya, M., Nakao, K., Sakahara, M., Watanabe, M., et al. (2008). Rac1 in cortical projection neurons is selectively required for midline crossing of commissural axonal formation. The European Journal of Neuroscience, 28(2), 257–267.PubMedGoogle Scholar
  76. 76.
    Nguyen, L., Besson, A., Heng, J. I., Schuurmans, C., Teboul, L., Parras, C., et al. (2006). p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes & Development, 20(11), 1511–1524.Google Scholar
  77. 77.
    Tang, J., Ip, J. P., Ye, T., Ng, Y. P., Yung, W. H., Wu, Z., et al. (2014). Cdk5-dependent Mst3 phosphorylation and activity regulate neuronal migration through RhoA inhibition. The Journal of Neuroscience, 34(22), 7425–7436.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Cappello, S., Bohringer, C. R., Bergami, M., Conzelmann, K. K., Ghanem, A., Tomassy, G. S., et al. (2012). A radial glia-specific role of RhoA in double cortex formation. Neuron, 73(5), 911–924.PubMedGoogle Scholar
  79. 79.
    Ho, T. T., Merajver, S. D., Lapiere, C. M., Nusgens, B. V., & Deroanne, C. F. (2008). RhoA-GDP regulates RhoB protein stability. Potential involvement of RhoGDIalpha. The Journal of Biological Chemistry, 283(31), 21588–21598.PubMedGoogle Scholar
  80. 80.
    Newey, S. E., Velamoor, V., Govek, E. E., & Van Aelst, L. (2005). Rho GTPases, dendritic structure, and mental retardation. Journal of Neurobiology, 64(1), 58–74.PubMedGoogle Scholar
  81. 81.
    Govek, E. E., Newey, S. E., & Van Aelst, L. (2005). The role of the Rho GTPases in neuronal development. Genes & Development, 19(1), 1–49.Google Scholar
  82. 82.
    Gu, H., Yu, S. P., Gutekunst, C. A., Gross, R. E., & Wei, L. (2013). Inhibition of the Rho signaling pathway improves neurite outgrowth and neuronal differentiation of mouse neural stem cells. International Journal of Physiology, Pathophysiology and Pharmacology, 5(1), 11–20.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Jeon, C. Y., Moon, M. Y., Kim, J. H., Kim, H. J., Kim, J. G., Li, Y., et al. (2012). Control of neurite outgrowth by RhoA inactivation. Journal of Neurochemistry, 120(5), 684–698.PubMedGoogle Scholar
  84. 84.
    Garvalov, B. K., Flynn, K. C., Neukirchen, D., Meyn, L., Teusch, N., Wu, X., et al. (2007). Cdc42 regulates cofilin during the establishment of neuronal polarity. The Journal of Neuroscience, 27(48), 13117–13129.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Rosario, M., Schuster, S., Juttner, R., Parthasarathy, S., Tarabykin, V., & Birchmeier, W. (2012). Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin. Genes & Development, 26(15), 1743–1757.Google Scholar
  86. 86.
    Yokota, Y., Eom, T. Y., Stanco, A., Kim, W. Y., Rao, S., Snider, W. D., et al. (2010). Cdc42 and Gsk3 modulate the dynamics of radial glial growth, inter-radial glial interactions and polarity in the developing cerebral cortex. Development, 137(23), 4101–4110.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Gleeson, J. G., & Walsh, C. A. (2000). Neuronal migration disorders: From genetic diseases to developmental mechanisms. Trends in Neurosciences, 23(8), 352–359.PubMedGoogle Scholar
  88. 88.
    Desikan, R. S., & Barkovich, A. J. (2016). Malformations of cortical development. Annals of Neurology, 80(6), 797–810.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Shu, T., 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.PubMedGoogle Scholar
  90. 90.
    Jiang, X., & Nardelli, J. (2016). Cellular and molecular introduction to brain development. Neurobiology of Disease, 92(Pt A), 3–17.PubMedGoogle Scholar
  91. 91.
    Lasser, M., Tiber, J., & Lowery, L. A. (2018). The role of the microtubule cytoskeleton in neurodevelopmental disorders. Frontiers in Cellular Neuroscience, 12, 165.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Parrini, E., Conti, V., Dobyns, W. B., & Guerrini, R. (2016). Genetic basis of brain malformations. Molecular Syndromology, 7(4), 220–233.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Chang, B. S., Duzcan, F., Kim, S., Cinbis, M., Aggarwal, A., Apse, K. A., et al. (2007). The role of RELN in lissencephaly and neuropsychiatric disease. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(1), 58–63.Google Scholar
  94. 94.
    Crino, P. (2001). New Reln mutation associated with lissencephaly and epilepsy. Epilepsy Currents, 1(2), 72.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Riikonen, R. (2017). Insulin-like growth factors in the pathogenesis of neurological diseases in children. International Journal of Molecular Sciences, 18(10), 2056.PubMedCentralGoogle Scholar
  96. 96.
    Sheen, V. L. (2012). Periventricular heterotopia: Shuttling of proteins through vesicles and actin in cortical development and disease. Scientifica, 2012, 480129.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., et al. (1998). Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron, 21(6), 1315–1325.PubMedGoogle Scholar
  98. 98.
    Riviere, J. B., van Bon, B. W., Hoischen, A., Kholmanskikh, S. S., O'Roak, B. J., Gilissen, C., et al. (2012). De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nature Genetics, 44(4), 440–444, S1-2.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Di Donato, N., Rump, A., Koenig, R., Der Kaloustian, V. M., Halal, F., Sonntag, K., et al. (2014). Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. European Journal of Human Genetics, 22(2), 179–183.PubMedGoogle Scholar
  100. 100.
    Uppal, N., & Hof, P. R. (2013). Chapter 3.6 - Discrete cortical neuropathology in autism spectrum disorders. In The neuroscience of autism spectrum disorders (pp. 313–325). San Diego: Academic Press.Google Scholar
  101. 101.
    Schumann, C. M., Noctor, S. C., & Amaral, D. G. (2011). Autism spectrum disorders. In D. G. Amaral, D. Geschwind, & D. Dawson (Eds.), Neuropathology of autism spectrum disorders: Postmortem studies. Oxford: Oxford University Press.Google Scholar
  102. 102.
    Amaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008). Neuroanatomy of autism. Trends in Neurosciences, 31(3), 137–145.PubMedGoogle Scholar
  103. 103.
    Blatt, G. J. (2012). The neuropathology of autism. Scientifica, 2012, 703675.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Bauman, M. L., & Kemper, T. L. (2005). Neuroanatomic observations of the brain in autism: A review and future directions. International Journal of Developmental Neuroscience, 23(2–3), 183–187.PubMedGoogle Scholar
  105. 105.
    Varghese, M., Keshav, N., Jacot-Descombes, S., Warda, T., Wicinski, B., Dickstein, D. L., et al. (2017). Autism spectrum disorder: Neuropathology and animal models. Acta Neuropathologica, 134(4), 537–566.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Schumann, C. M., & Nordahl, C. W. (2011). Bridging the gap between MRI and postmortem research in autism. Brain Research, 1380, 175–186.PubMedGoogle Scholar
  107. 107.
    Hampson, D. R., & Blatt, G. J. (2015). Autism spectrum disorders and neuropathology of the cerebellum. Frontiers in Neuroscience, 9, 420.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Gadad, B. S., Hewitson, L., Young, K. A., & German, D. C. (2013). Neuropathology and animal models of autism: Genetic and environmental factors. Autism Research and Treatment, 2013, 731935.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Santos, M., Uppal, N., Butti, C., Wicinski, B., Schmeidler, J., Giannakopoulos, P., et al. (2011). Von Economo neurons in autism: A stereologic study of the frontoinsular cortex in children. Brain Research, 1380, 206–217.PubMedGoogle Scholar
  110. 110.
    Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Wegiel, J., Marchi, E., et al. (2010). The neuropathology of autism: Defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathologica, 119(6), 755–770.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Fatemi, S. H., & Folsom, T. D. (2009). The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophrenia Bulletin, 35(3), 528–548.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Chen, R., Jiao, Y., & Herskovits, E. H. (2011). Structural MRI in autism spectrum disorder. Pediatric Research, 69(5 Pt 2), 63R–68R.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Kucharsky Hiess, R., Alter, R., Sojoudi, S., Ardekani, B. A., Kuzniecky, R., & Pardoe, H. R. (2015). Corpus callosum area and brain volume in autism spectrum disorder: Quantitative analysis of structural MRI from the ABIDE database. Journal of Autism and Developmental Disorders, 45(10), 3107–3114.PubMedGoogle Scholar
  114. 114.
    Schumann, C. M., Bloss, C. S., Barnes, C. C., Wideman, G. M., Carper, R. A., Akshoomoff, N., et al. (2010). Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism. The Journal of Neuroscience, 30(12), 4419–4427.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Zielinski, B. A., Prigge, M. B., Nielsen, J. A., Froehlich, A. L., Abildskov, T. J., Anderson, J. S., et al. (2014). Longitudinal changes in cortical thickness in autism and typical development. Brain, 137(Pt 6), 1799–1812.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Dementieva, Y. A., Vance, D. D., Donnelly, S. L., Elston, L. A., Wolpert, C. M., Ravan, S. A., et al. (2005). Accelerated head growth in early development of individuals with autism. Pediatric Neurology, 32(2), 102–108.PubMedGoogle Scholar
  117. 117.
    Fombonne, E., Roge, B., Claverie, J., Courty, S., & Fremolle, J. (1999). Microcephaly and macrocephaly in autism. Journal of Autism and Developmental Disorders, 29(2), 113–119.PubMedGoogle Scholar
  118. 118.
    Anagnostou, E., & Taylor, M. J. (2011). Review of neuroimaging in autism spectrum disorders: What have we learned and where we go from here. Molecular Autism, 2(1), 4.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hardan, A. Y., Pabalan, M., Gupta, N., Bansal, R., Melhem, N. M., Fedorov, S., et al. (2009). Corpus callosum volume in children with autism. Psychiatry Research, 174(1), 57–61.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Frazier, T. W., & Hardan, A. Y. (2009). A meta-analysis of the corpus callosum in autism. Biological Psychiatry, 66(10), 935–941.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Stanfield, A. C., McIntosh, A. M., Spencer, M. D., Philip, R., Gaur, S., & Lawrie, S. M. (2008). Towards a neuroanatomy of autism: A systematic review and meta-analysis of structural magnetic resonance imaging studies. European Psychiatry, 23(4), 289–299.PubMedGoogle Scholar
  122. 122.
    Ameis, S. H., Fan, J., Rockel, C., Voineskos, A. N., Lobaugh, N. J., Soorya, L., et al. (2011). Impaired structural connectivity of socio-emotional circuits in autism spectrum disorders: A diffusion tensor imaging study. PLoS One, 6(11), e28044.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Hardan, A. Y., Libove, R. A., Keshavan, M. S., Melhem, N. M., & Minshew, N. J. (2009). A preliminary longitudinal magnetic resonance imaging study of brain volume and cortical thickness in autism. Biological Psychiatry, 66(4), 320–326.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Neale, B. M., Kou, Y., Liu, L., Ma'ayan, A., Samocha, K. E., Sabo, A., et al. (2012). Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature, 485(7397), 242–245.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Deriziotis, P., O'Roak, B. J., Graham, S. A., Estruch, S. B., Dimitropoulou, D., Bernier, R. A., et al. (2014). De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature Communications, 5, 4954.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Huang, T. N., & Hsueh, Y. P. (2015). Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders. Frontiers in Neuroscience, 9, 406.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Traylor, R. N., Dobyns, W. B., Rosenfeld, J. A., Wheeler, P., Spence, J. E., Bandholz, A. M., et al. (2012). Investigation of TBR1 hemizygosity: Four individuals with 2q24 microdeletions. Molecular Syndromology, 3(3), 102–112.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Hamdan, F. F., Srour, M., Capo-Chichi, J. M., Daoud, H., Nassif, C., Patry, L., et al. (2014). De novo mutations in moderate or severe intellectual disability. PLoS Genetics, 10(10), e1004772.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Bedogni, F., Hodge, R. D., Elsen, G. E., Nelson, B. R., Daza, R. A., Beyer, R. P., et al. (2010). Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proceedings of the National Academy of Sciences of the United States of America, 107(29), 13129–13134.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Packer, A. (2016). Neocortical neurogenesis and the etiology of autism spectrum disorder. Neuroscience and Biobehavioral Reviews, 64, 185–195.Google Scholar
  131. 131.
    Gallagher, D., Voronova, A., Zander, M. A., Cancino, G. I., Bramall, A., Krause, M. P., et al. (2015). Ankrd11 is a chromatin regulator involved in autism that is essential for neural development. Developmental Cell, 32(1), 31–42.PubMedGoogle Scholar
  132. 132.
    De Rubeis, S., He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Cicek, A. E., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209–215.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., Samocha, K. E., Cicek, A. E., et al. (2015). Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron, 87(6), 1215–1233.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Tuoc, T. C., Narayanan, R., & Stoykova, A. (2013). BAF chromatin remodeling complex: Cortical size regulation and beyond. Cell Cycle, 12(18), 2953–2959.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Tuoc, T. C., Boretius, S., Sansom, S. N., Pitulescu, M. E., Frahm, J., Livesey, F. J., et al. (2013). Chromatin regulation by BAF170 controls cerebral cortical size and thickness. Developmental Cell, 25(3), 256–269.PubMedGoogle Scholar
  136. 136.
    Chen, Y., Huang, W. C., Sejourne, J., Clipperton-Allen, A. E., & Page, D. T. (2015). Pten mutations Alter brain growth trajectory and allocation of cell types through elevated beta-catenin signaling. The Journal of Neuroscience, 35(28), 10252–10267.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Strauss, K. A., Puffenberger, E. G., Huentelman, M. J., Gottlieb, S., Dobrin, S. E., Parod, J. M., et al. (2006). Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. The New England Journal of Medicine, 354(13), 1370–1377.PubMedGoogle Scholar
  138. 138.
    Bakkaloglu, B., O'Roak, B. J., Louvi, A., Gupta, A. R., Abelson, J. F., Morgan, T. M., et al. (2008). Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. American Journal of Human Genetics, 82(1), 165–173.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Alarcon, M., Abrahams, B. S., Stone, J. L., Duvall, J. A., Perederiy, J. V., Bomar, J. M., et al. (2008). Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. American Journal of Human Genetics, 82(1), 150–159.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Conti, S., Condo, M., Posar, A., Mari, F., Resta, N., Renieri, A., et al. (2012). Phosphatase and tensin homolog (PTEN) gene mutations and autism: Literature review and a case report of a patient with Cowden syndrome, autistic disorder, and epilepsy. Journal of Child Neurology, 27(3), 392–397.PubMedGoogle Scholar
  141. 141.
    Wiegreffe, C., Simon, R., Peschkes, K., Kling, C., Strehle, M., Cheng, J., et al. (2015). Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c. Neuron, 87(2), 311–325.PubMedGoogle Scholar
  142. 142.
    Li, X., Xiao, J., Frohlich, H., Tu, X., Li, L., Xu, Y., et al. (2015). Foxp1 regulates cortical radial migration and neuronal morphogenesis in developing cerebral cortex. PLoS One, 10(5), e0127671e.Google Scholar
  143. 143.
    Miyoshi, G., & Fishell, G. (2012). Dynamic FoxG1 expression coordinates the integration of multipolar pyramidal neuron precursors into the cortical plate. Neuron, 74(6), 1045–1058.PubMedPubMedCentralGoogle Scholar
  144. 144.
    La Fata, G., Gartner, A., Dominguez-Iturza, N., Dresselaers, T., Dawitz, J., Poorthuis, R. B., et al. (2014). FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry. Nature Neuroscience, 17(12), 1693–1700.PubMedGoogle Scholar
  145. 145.
    Boitard, M., Bocchi, R., Egervari, K., Petrenko, V., Viale, B., Gremaud, S., et al. (2015). Wnt signaling regulates multipolar-to-bipolar transition of migrating neurons in the cerebral cortex. Cell Reports, 10(8), 1349–1361.PubMedGoogle Scholar
  146. 146.
    Hori, K., & Hoshino, M. (2017). Neuronal migration and AUTS2 syndrome. Brain Sciences, 7(12), 54.PubMedCentralGoogle Scholar
  147. 147.
    Hori, K., Nagai, T., Shan, W., Sakamoto, A., Taya, S., Hashimoto, R., et al. (2014). Cytoskeletal regulation by AUTS2 in neuronal migration and neuritogenesis. Cell Reports, 9(6), 2166–2179.PubMedGoogle Scholar
  148. 148.
    Yoo, H. (2015). Genetics of autism Spectrum disorder: Current status and possible clinical applications. Exp Neurobiol., 24(4), 257–272.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Buxbaum, J. D. (2009). Multiple rare variants in the etiology of autism spectrum disorders. Dialogues in Clinical Neuroscience, 11(1), 35–43.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Weiner, D. J., Wigdor, E. M., Ripke, S., Walters, R. K., Kosmicki, J. A., Grove, J., et al. (2017). Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nature Genetics, 49(7), 978–985.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Bray, N. (2017). Neurodevelopmental disorders: Converging on autism spectrum disorder. Nature Reviews. Neuroscience, 18(2), 67.PubMedGoogle Scholar
  152. 152.
    Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., et al. (2014). Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. American Journal of Human Genetics, 94(5), 677–694.PubMedPubMedCentralGoogle Scholar
  153. 153.
    Berg, J. M., & Geschwind, D. H. (2012). Autism genetics: Searching for specificity and convergence. Genome Biology, 13(7), 247.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Gupta, S., Ellis, S. E., Ashar, F. N., Moes, A., Bader, J. S., Zhan, J., et al. (2014). Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nature Communications, 5, 5748.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Gokoolparsadh, A., Sutton, G. J., Charamko, A., Green, N. F., Pardy, C. J., & Voineagu, I. (2016). Searching for convergent pathways in autism spectrum disorders: Insights from human brain transcriptome studies. Cellular and Molecular Life Sciences, 73(23), 4517–4530.PubMedGoogle Scholar
  156. 156.
    Voineagu, I., & Eapen, V. (2013). Converging pathways in autism spectrum disorders: Interplay between synaptic dysfunction and immune responses. Frontiers in Human Neuroscience, 7, 738.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Voineagu, I., Wang, X., Johnston, P., Lowe, J. K., Tian, Y., Horvath, S., et al. (2011). Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature, 474(7351), 380–384.PubMedPubMedCentralGoogle Scholar
  158. 158.
    Wen, Y., Alshikho, M. J., & Herbert, M. R. (2016). Pathway network analyses for autism reveal multisystem involvement, major overlaps with other diseases and convergence upon MAPK and calcium signaling. PLoS One, 11(4), e0153329.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Luo, W., Zhang, C., Jiang, Y. H., & Brouwer, C. R. (2018). Systematic reconstruction of autism biology from massive genetic mutation profiles. Science Advances, 4(4), e1701799.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Sanders, S. J. (2015). First glimpses of the neurobiology of autism spectrum disorder. Current Opinion in Genetics & Development, 33, 80–92.Google Scholar
  161. 161.
    Ernst, C. (2016). Proliferation and differentiation deficits are a major convergence point for neurodevelopmental disorders. Trends in Neurosciences, 39(5), 290–299.PubMedGoogle Scholar
  162. 162.
    Stevens, H. E., Smith, K. M., Rash, B. G., & Vaccarino, F. M. (2010). Neural stem cell regulation, fibroblast growth factors, and the developmental origins of neuropsychiatric disorders. Frontiers in Neuroscience, 4, 59.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Sacco, R., Cacci, E., & Novarino, G. (2018). Neural stem cells in neuropsychiatric disorders. Current Opinion in Neurobiology, 48, 131–138.PubMedGoogle Scholar
  164. 164.
    Willsey, A. J., Sanders, S. J., Li, M., Dong, S., Tebbenkamp, A. T., Muhle, R. A., et al. (2013). Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell, 155(5), 997–1007.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Parikshak, N. N., Luo, R., Zhang, A., Won, H., Lowe, J. K., Chandran, V., et al. (2013). Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell, 155(5), 1008–1021.PubMedPubMedCentralGoogle Scholar
  166. 166.
    Sara Ballouz, Paul Pavlidis, Jesse Gillis, Using predictive specificity to determine when gene set analysis is biologically meaningful. Nucleic Acids Research:gkw957.Google Scholar
  167. 167.
    Satterstrom F. K., Kosmicki J A., Wang J, Breen M S., De Rubeis S, Joon-Yong An, et al. (2020) Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Cell 180(3):568–584.e23PubMedGoogle Scholar
  168. 168.
    Gandal, M. J., Haney, J. R., Parikshak, N. N., Leppa, V., Ramaswami, G., Hartl, C., et al. (2018). Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science, 359(6376), 693–697.PubMedPubMedCentralGoogle Scholar
  169. 169.
    Hoeffer, C. A., Sanchez, E., Hagerman, R. J., Mu, Y., Nguyen, D. V., Wong, H., et al. (2012). Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes, Brain, and Behavior, 11(3), 332–341.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Olson, C. O., Pejhan, S., Kroft, D., Sheikholeslami, K., Fuss, D., Buist, M., et al. (2018). MECP2 mutation interrupts nucleolin-mTOR-P70S6K Signaling in Rett syndrome patients. Frontiers in Genetics, 9, 635.PubMedPubMedCentralGoogle Scholar
  171. 171.
    Ricciardi, S., Boggio, E. M., Grosso, S., Lonetti, G., Forlani, G., Stefanelli, G., et al. (2011). Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Human Molecular Genetics, 20(6), 1182–1196.PubMedGoogle Scholar
  172. 172.
    Xing, X., Zhang, J., Wu, K., Cao, B., Li, X., Jiang, F., et al. (2019). Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice. Scientific Reports, 9(1), 3041.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Rosina, E., Battan, B., Siracusano, M., Di Criscio, L., Hollis, F., Pacini, L., et al. (2019). Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Translational Psychiatry, 9(1), 50.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.PubMedGoogle Scholar
  175. 175.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.PubMedGoogle Scholar
  176. 176.
    Yamanaka, S. (2006). Molecular mechanisms underlying pluripotency of embryonic stem cells. Seikagaku, 78(1), 27–33.PubMedGoogle Scholar
  177. 177.
    Okita, K., & Yamanaka, S. (2006). Intracellular signaling pathways regulating pluripotency of embryonic stem cells. Current Stem Cell Research & Therapy, 1(1), 103–111.Google Scholar
  178. 178.
    Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., et al. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnology, 26(1), 101–106.PubMedGoogle Scholar
  179. 179.
    Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Marchetto, M. C., Carromeu, C., Acab, A., Yu, D., Yeo, G. W., Mu, Y., et al. (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4), 527–539.PubMedPubMedCentralGoogle Scholar
  181. 181.
    Pasca, S. P., Portmann, T., Voineagu, I., Yazawa, M., Shcheglovitov, A., Pasca, A. M., et al. (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Medicine, 17(12), 1657–1662.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Urbach, A., Bar-Nur, O., Daley, G. Q., & Benvenisty, N. (2010). Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell, 6(5), 407–411.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Krey, J. F., Pasca, S. P., Shcheglovitov, A., Yazawa, M., Schwemberger, R., Rasmusson, R., et al. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nature Neuroscience, 16(2), 201–209.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Tian, Y., Voineagu, I., Pasca, S. P., Won, H., Chandran, V., Horvath, S., et al. (2014). Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Medicine, 6(10), 75.PubMedPubMedCentralGoogle Scholar
  185. 185.
    Mor-Shaked, H., & Eiges, R. (2016). Modeling fragile X syndrome using human pluripotent stem cells. Genes, 7(10), 77.PubMedCentralGoogle Scholar
  186. 186.
    Li, M., Zhao, H., Ananiev, G. E., Musser, M. T., Ness, K. H., Maglaque, D. L., et al. (2017). Establishment of reporter lines for detecting fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells, 35(1), 158–169.PubMedGoogle Scholar
  187. 187.
    Bhattacharyya, A., & Zhao, X. (2016). Human pluripotent stem cell models of Fragile X syndrome. Molecular and Cellular Neurosciences, 73, 43–51.PubMedGoogle Scholar
  188. 188.
    Doers, M. E., Musser, M. T., Nichol, R., Berndt, E. R., Baker, M., Gomez, T. M., et al. (2014). iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells and Development, 23(15), 1777–1787.PubMedPubMedCentralGoogle Scholar
  189. 189.
    Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., et al. (2013). SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature, 503(7475), 267–271.PubMedPubMedCentralGoogle Scholar
  190. 190.
    Yi, F., Danko, T., Botelho, S. C., Patzke, C., Pak, C., Wernig, M., et al. (2016). Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science, 352(6286), aaf2669.PubMedPubMedCentralGoogle Scholar
  191. 191.
    Kathuria, A., Nowosiad, P., Jagasia, R., Aigner, S., Taylor, R. D., Andreae, L. C., et al. (2018). Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development. Molecular Psychiatry, 23(3), 735–746.Google Scholar
  192. 192.
    Deshpande, A., Yadav, S., Dao, D. Q., Wu, Z. Y., Hokanson, K. C., Cahill, M. K., et al. (2017). Cellular phenotypes in human iPSC-derived neurons from a genetic model of autism spectrum disorder. Cell Reports, 21(10), 2678–2687.PubMedPubMedCentralGoogle Scholar
  193. 193.
    Flaherty, E., Deranieh, R. M., Artimovich, E., Lee, I. S., Siegel, A. J., Levy, D. L., et al. (2017). Patient-derived hiPSC neurons with heterozygous CNTNAP2 deletions display altered neuronal gene expression and network activity. NPJ Schizophrenia, 3, 35.PubMedPubMedCentralGoogle Scholar
  194. 194.
    Brennand, K. J., Simone, A., Jou, J., Gelboin-Burkhart, C., Tran, N., Sangar, S., et al. (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature, 473(7346), 221–225.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Brennand, K., Savas, J. N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., et al. (2015). Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry, 20(3), 361–368.PubMedGoogle Scholar
  196. 196.
    Griesi-Oliveira, K., Acab, A., Gupta, A. R., Sunaga, D. Y., Chailangkarn, T., Nicol, X., et al. (2015). Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Molecular Psychiatry, 20(11), 1350–1365.PubMedGoogle Scholar
  197. 197.
    Mariani, J., Coppola, G., Zhang, P., Abyzov, A., Provini, L., Tomasini, L., et al. (2015). FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell, 162(2), 375–390.PubMedPubMedCentralGoogle Scholar
  198. 198.
    Marchetto, M. C., Belinson, H., Tian, Y., Freitas, B. C., Fu, C., Vadodaria, K., et al. (2017). Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Molecular Psychiatry, 22(6), 820–835.Google Scholar
  199. 199.
    Liu, X., Campanac, E., Cheung, H. H., Ziats, M. N., Canterel-Thouennon, L., Raygada, M., et al. (2017). Idiopathic autism: Cellular and molecular phenotypes in pluripotent stem cell-derived neurons. Molecular Neurobiology, 54(6), 4507–4523.PubMedGoogle Scholar
  200. 200.
    Stadtfeld, M., & Hochedlinger, K. (2010). Induced pluripotency: History, mechanisms, and applications. Genes & Development, 24(20), 2239–2263.Google Scholar
  201. 201.
    Schwartzentruber, J., Foskolou, S., Kilpinen, H., Rodrigues, J., Alasoo, K., Knights, A. J., et al. (2018). Molecular and functional variation in iPSC-derived sensory neurons. Nature Genetics, 50(1), 54–61.PubMedGoogle Scholar
  202. 202.
    Vitale, A. M., Matigian, N. A., Ravishankar, S., Bellette, B., Wood, S. A., Wolvetang, E. J., et al. (2012). Variability in the generation of induced pluripotent stem cells: Importance for disease modeling. Stem Cells Translational Medicine, 1(9), 641–650.PubMedPubMedCentralGoogle Scholar
  203. 203.
    Vigilante, A., Laddach, A., Moens, N., Meleckyte, R., Leha, A., Ghahramani, A., et al. (2019). Identifying extrinsic versus intrinsic drivers of variation in cell behavior in human iPSC lines from healthy donors. Cell Reports, 26(8), 2078–2087. e3.PubMedPubMedCentralGoogle Scholar
  204. 204.
    Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., et al. (2017). Analysis of transcriptional variability in a large human iPSC library reveals genetic and non-genetic determinants of heterogeneity. Cell Stem Cell, 20(4), 518–532. e9.PubMedGoogle Scholar
  205. 205.
    Volpato, V., Smith, J., Sandor, C., Ried, J. S., Baud, A., Handel, A., et al. (2018). Reproducibility of molecular phenotypes after long-term differentiation to human iPSC-derived neurons: A multi-site omics study. Stem Cell Reports, 11(4), 897–911.PubMedPubMedCentralGoogle Scholar
  206. 206.
    Deng, J., Shoemaker, R., Xie, B., Gore, A., LeProust, E. M., Antosiewicz-Bourget, J., et al. (2009). Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nature Biotechnology, 27(4), 353–360.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Doi, A., Park, I. H., Wen, B., Murakami, P., Aryee, M. J., Irizarry, R., et al. (2009). Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genetics, 41(12), 1350–1353.PubMedPubMedCentralGoogle Scholar
  208. 208.
    Lister, R., Pelizzola, M., Kida, Y. S., Hawkins, R. D., Nery, J. R., Hon, G., et al. (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature, 471(7336), 68–73.PubMedPubMedCentralGoogle Scholar
  209. 209.
    Kim, K., Doi, A., Wen, B., Ng, K., Zhao, R., Cahan, P., et al. (2010). Epigenetic memory in induced pluripotent stem cells. Nature, 467(7313), 285–290.PubMedPubMedCentralGoogle Scholar
  210. 210.
    Polo, J. M., Liu, S., Figueroa, M. E., Kulalert, W., Eminli, S., Tan, K. Y., et al. (2010). Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nature Biotechnology, 28(8), 848–855.PubMedPubMedCentralGoogle Scholar
  211. 211.
    Falk, A., Heine, V. M., Harwood, A. J., Sullivan, P. F., Peitz, M., Brüstle, O., Shen, S., Sun, Y-M., Glover, J. C., Posthuma, D., Djurovic, S. (2016) Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Molecular Psychiatry 21(9):1167–1179.PubMedPubMedCentralGoogle Scholar
  212. 212.
    Halevy, T., & Urbach, A. (2014). Comparing ESC and iPSC-based models for human genetic disorders. Journal of Clinical Medicine, 3(4), 1146–1162.PubMedPubMedCentralGoogle Scholar
  213. 213.
    Williams, M., Prem, S., Zhou, X., Matteson, P., Yeung, P. L., & Lu, C. W., et al. (2018). Rapid detection of neurodevelopmental phenotypes in human neural precursor cells (NPCs). Journal of Visualized Experiments (133).  https://doi.org/10.3791/56628
  214. 214.
    Rossman, I. T., Lin, L., Morgan, K. M., Digiovine, M., Van Buskirk, E. K., Kamdar, S., et al. (2014). Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development. Molecular Autism, 5(1), 9.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Smrithi Prem
    • 1
  • James H. Millonig
    • 2
  • Emanuel DiCicco-Bloom
    • 3
    Email author
  1. 1.Graduate Program in NeuroscienceRutgers UniversityPiscatawayUSA
  2. 2.Department of Neuroscience and Cell Biology, Center for Advanced Biotechnology and Medicine, Rutgers Robert Wood Johnson Medical SchoolRutgers UniversityPiscatawayUSA
  3. 3.Department of Neuroscience and Cell Biology/PediatricsRutgers Robert Wood Johnson Medical School, Rutgers UniversityPiscatawayUSA

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