NeuroMolecular Medicine

, Volume 17, Issue 3, pp 297–304 | Cite as

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

  • Jan Bakos
  • Zuzana Bacova
  • Stephen G. Grant
  • Ana M. Castejon
  • Daniela Ostatnikova
Original Paper

Abstract

Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

Keywords

Autism Neurites Brain development Biomarkers Cytoskeletal remodeling 

Notes

Acknowledgments

The work was supported by the Slovak Research and Development Agency projects APVV-0253-10 and APVV-0254-11.

References

  1. Alter, M. D., Kharkar, R., Ramsey, K. E., Craig, D. W., Melmed, R. D., Grebe, T. A., et al. (2011). Autism and increased paternal age related changes in global levels of gene expression regulation. PLoS One, 6(2), e16715.PubMedCentralCrossRefPubMedGoogle Scholar
  2. Auer, M., Schweigreiter, R., Hausott, B., Thongrong, S., Höltje, M., Just, I., et al. (2012). Rho-independent stimulation of axon outgrowth and activation of the ERK and Akt signaling pathways by C3 transferase in sensory neurons. Frontiers in Cellular Neuroscience, 6, 43.PubMedCentralCrossRefPubMedGoogle Scholar
  3. Billeci, L., Calderoni, S., Tosetti, M., Catani, M., & Muratori, F. (2012). White matter connectivity in children with autism spectrum disorders: A tract-based spatial statistics study. BMC Neurology, 12, 148.PubMedCentralCrossRefPubMedGoogle Scholar
  4. Birnbaum, R., Jaffe, A. E., Hyde, T. M., Kleinman, J. E., & Weinberger, D. R. (2014). Prenatal expression patterns of genes associated with neuropsychiatric disorders. American Journal of Psychiatry, 171(7), 758–767.PubMedCentralCrossRefPubMedGoogle Scholar
  5. Burton, E. A., Oliver, T. N., & Pendergast, A. M. (2005). Abl kinases regulate actin comet tail elongation via an N-WASP-dependent pathway. Molecular and Cellular Biology, 25(20), 8834–8843.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Carroll, D., Hallett, V., McDougle, C. J., Aman, M. G., McCracken, J. T., Tierney, E., et al. (2014). Examination of aggression and self-injury in children with autism spectrum disorders and serious behavioral problems. Child and Adolescent Psychiatric Clinics of North America, 23(1), 57–72.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Castermans, D., Volders, K., Crepel, A., Backx, L., De Vos, R., Freson, K., et al. (2010). SCAMP5, NBEA and AMISYN: Three candidate genes for autism involved in secretion of large dense-core vesicles. Human Molecular Genetics, 19(7), 1368–1378.CrossRefPubMedGoogle Scholar
  8. Chang, Y. C., Tien, S. C., Tien, H. F., Zhang, H., Bokoch, G. M., & Chang, Z. F. (2009). p210 (Bcr-Abl) desensitizes Cdc42 GTPase signaling for SDF-1alpha-directed migration in chronic myeloid leukemia cells. Oncogene, 28(46), 4105–4115.CrossRefPubMedGoogle Scholar
  9. Corvin, A. P. (2010). Neuronal cell adhesion genes: Key players in risk for schizophrenia, bipolar disorder and other neurodevelopmental brain disorders?. Cell Adhesion and Migration, 4(4), 511–514.PubMedCentralCrossRefPubMedGoogle Scholar
  10. Courchesne, E., Carper, R., & Akshoomoff, N. (2003). Evidence of brain overgrowth in the first year of life in autism. Journal of the American Medical Association, 290(3), 337–344.CrossRefPubMedGoogle Scholar
  11. da Silva, J. S., & Dotti, C. G. (2002). Breaking the neuronal sphere: Regulation of the actin cytoskeleton in neuritogenesis. Nature Reviews Neuroscience, 3(9), 694–704.CrossRefPubMedGoogle Scholar
  12. Dehmelt, L., & Halpain, S. (2004). Actin and microtubules in neurite initiation: Are MAPs the missing link? Journal of Neurobiology, 58(1), 18–33.CrossRefPubMedGoogle Scholar
  13. Dehmelt, L., Nalbant, P., Steffen, W., & Halpain, S. (2006). A microtubule-based, dynein-dependent force induces local cell protrusions: Implications for neurite initiation. Brain Cell Biology, 35(1), 39–56.CrossRefPubMedGoogle Scholar
  14. Dent, E. W., Gupton, S. L., & Gertler, F. B. (2011). The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harbor Perspectives in Biology, 3(3), a001800.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Dotti, C. G., Sullivan, C. A., & Banker, G. A. (1988). The establishment of polarity by hippocampal neurons in culture. Journal of Neuroscience, 8(4), 1454–1468.PubMedGoogle Scholar
  16. Drees, F., & Gertler, F. B. (2008). Ena/VASP: proteins at the tip of the nervous system. Current Opinion in Neurobiology, 18(1), 53–59.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Edwards, T. J., Sherr, E. H., Barkovich, A. J., & Richards, L. J. (2014). Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain, 137(6), 1579–1613.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Goldberg, D., Borojevic, R., Anderson, M., Chen, J. J., Gershon, M. D., & Ratcliffe, E. M. (2013). Slit/Robo-mediated chemorepulsion of vagal sensory axons in the fetal gut. Developmental Dynamics, 242(1), 9–15.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Govek, E. E., Newey, S. E., & Van Aelst, L. (2005). The role of the Rho GTPases in neuronal development. Genes and Development, 19(1), 1–49.CrossRefPubMedGoogle Scholar
  20. Gregg, J. P., Lit, L., Baron, C. A., Hertz-Picciotto, I., Walker, W., Davis, R. A., et al. (2008). Gene expression changes in children with autism. Genomics, 91(1), 22–29.CrossRefPubMedGoogle Scholar
  21. Grice, D. E., & Buxbaum, J. D. (2006). The genetics of autism spectrum disorders. NeuroMolecular Medicine, 8(4), 451–460.CrossRefPubMedGoogle Scholar
  22. Grosshans, B. L., Ortiz, D., & Novick, P. (2006). Rabs and their effectors: achieving specificity in membrane traffic. Proceedings of the National Academy of Sciences of the United States of America, 103(32), 11821–11827.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Hall, A., & Lalli, G. (2010). Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harbor Perspectives in Biology, 2(2), a001818.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Hammond, R., Vivancos, V., Naeem, A., Chilton, J., Mambetisaeva, E., Andrews, W., et al. (2005). Slit-mediated repulsion is a key regulator of motor axon pathfinding in the hindbrain. Development, 132(20), 4483–4495.CrossRefPubMedGoogle Scholar
  25. Hirokawa, N., Niwa, S., & Tanaka, Y. (2010). Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron, 68(4), 610–638.CrossRefPubMedGoogle Scholar
  26. Horgan, C. P., & McCaffrey, M. W. (2011). Rab GTPases and microtubule motors. Biochemical Society Transactions, 39(5), 1202–1206.CrossRefPubMedGoogle Scholar
  27. Jou, R. J., Mateljevic, N., Kaiser, M. D., Sugrue, D. R., Volkmar, F. R., & Pelphrey, K. A. (2011). Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics. American Journal of Neuroradiology, 32(9), 1607–1613.CrossRefPubMedGoogle Scholar
  28. Just, M. A., Cherkassky, V. L., Keller, T. A., & Minshew, N. J. (2004). Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain, 127(8), 1811–1821.CrossRefPubMedGoogle Scholar
  29. Kollins, K. M., Bell, R. L., Butts, M., & Withers, G. S. (2009). Dendrites differ from axons in patterns of microtubule stability and polymerization during development. Neural Development, 4, 26.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Korey, C. A., & Van Vactor, D. (2000). From the growth cone surface to the cytoskeleton: one journey, many paths. Journal of Neurobiology, 44(2), 184–193.CrossRefPubMedGoogle Scholar
  31. Kozma, R., Sarner, S., Ahmed, S., & Lim, L. (1997). Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Molecular and Cellular Biology, 17(3), 1201–1211.PubMedCentralPubMedGoogle Scholar
  32. Krause, M., Leslie, J. D., Stewart, M., Lafuente, E. M., Valderrama, F., Jagannathan, R., et al. (2004). Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Developmental Cell, 7(4), 571–583.CrossRefPubMedGoogle Scholar
  33. Kwiatkowski, A. V., Rubinson, D. A., Dent, E. W., Edward van Veen, J., Leslie, J. D., Zhang, J., et al. (2007). Ena/VASP Is Required for neuritogenesis in the developing cortex. Neuron, 56(3), 441–455.CrossRefPubMedGoogle Scholar
  34. Lebrand, C., Dent, E. W., Strasser, G. A., Lanier, L. M., Krause, M., Svitkina, T. M., et al. (2004). Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1. Neuron, 42(1), 37–49.CrossRefPubMedGoogle Scholar
  35. Lepagnol-Bestel, A. M., Maussion, G., Boda, B., Cardona, A., Iwayama, Y., Delezoide, A. L., et al. (2008). SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects. Molecular Psychiatry, 13(4), 385–397.CrossRefPubMedGoogle Scholar
  36. Major, D. L., & Brady-Kalnay, S. M. (2007). Rho GTPases regulate PTPµ-mediated nasal neurite outgrowth and temporal repulsion of retinal ganglion cell neurons. Molecular and Cellular Neuroscience, 34(3), 453–467.PubMedCentralCrossRefPubMedGoogle Scholar
  37. Márquez, C., Poirier, G. L., Cordero, M. I., Larsen, M. H., Groner, A., Marquis, J., et al. (2013). Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Translational Psychiatry, 3, e216.PubMedCentralCrossRefPubMedGoogle Scholar
  38. Maximo, J. O., Cadena, E. J., & Kana, R. K. (2014). The implications of brain connectivity in the neuropsychology of autism. Neuropsychology Review, 24(1), 16–31.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Mercati, O., Danckaert, A., André-Leroux, G., Bellinzoni, M., Gouder, L., Watanabe, K., et al. (2013). Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites. Biology Open, 2(3), 324–334.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Millard, T. H., Sharp, S. J., & Machesky, L. M. (2004). Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochemical Journal, 380(1), 1–17.PubMedCentralCrossRefPubMedGoogle Scholar
  41. Moughamian, A. J., & Holzbaur, E. L. (2012). Dynactin is required for transport initiation from the distal axon. Neuron, 74(2), 331–343.PubMedCentralCrossRefPubMedGoogle Scholar
  42. Moughamian, A. J., Osborn, G. E., Lazarus, J. E., Maday, S., & Holzbaur, E. L. (2013). Ordered recruitment of dynactin to the microtubule plus-end is required for efficient initiation of retrograde axonal transport. Journal of Neuroscience, 33(32), 13190–13203.PubMedCentralCrossRefPubMedGoogle Scholar
  43. Murray, A., Naeem, A., Barnes, S. H., Drescher, U., & Guthrie, S. (2010). Slit and Netrin-1 guide cranial motor axon pathfinding via Rho-kinase, myosin light chain kinase and myosin II. Neural Development, 5, 16.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Oblander, S. A., & Brady-Kalnay, S. M. (2010). Distinct PTPµ-associated signaling molecules differentially regulate neurite outgrowth on E-, N-, and R-cadherin. Molecular and Cellular Neuroscience, 44(1), 78–93.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Paemka, L., Mahajan, V. B., Skeie, J. M., Sowers, L. P., Ehaideb, S. N., Gonzalez-Alegre, P., et al. (2013). PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. PLoS One, 8(12), e80737.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Peñagarikano, O., Abrahams, B. S., Herman, E. I., Winden, K. D., Gdalyahu, A., Dong, H., et al. (2011). Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell, 147(1), 235–246.PubMedCentralCrossRefPubMedGoogle Scholar
  47. Piton, A., Gauthier, J., Hamdan, F. F., Lafrenière, R. G., Yang, Y., Henrion, E., et al. (2011). Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Molecular Psychiatry, 16(8), 867–880.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Polleux, F., & Snider, W. (2010). Initiating and growing an axon. Cold Spring Harbor Perspectives in Biology, 2(4), a001925.PubMedCentralCrossRefPubMedGoogle Scholar
  49. Pommereit, D., & Wouters, F. S. (2007). An NGF-induced Exo70-TC10 complex locally antagonizes Cdc42-mediated activation of N-WASP to modulate neurite outgrowth. Journal of Cell Science, 120(15), 2694–2705.CrossRefPubMedGoogle Scholar
  50. Prokop, A. (2013). The intricate relationship between microtubules and their associated motor proteins during axon growth and maintenance. Neural Development, 8, 17.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Rohatgi, R., Ma, L., Miki, H., Lopez, M., Kirchhausen, T., Takenawa, T., & Kirschner, M. W. (1999). The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell, 97(2), 221–231.CrossRefPubMedGoogle Scholar
  52. Schaer, M., Ottet, M. C., Scariati, E., Dukes, D., Franchini, M., Eliez, S., & Glaser, B. (2013). Decreased frontal gyrification correlates with altered connectivity in children with autism. Frontiers in Human Neuroscience, 7, 750.PubMedCentralCrossRefPubMedGoogle Scholar
  53. Smith, L. G., & Li, R. (2004). Actin polymerization: Riding the wave. Current Biology, 14(3), R109–R111.CrossRefPubMedGoogle Scholar
  54. Su, Y. Y., Ye, M., Li, L., Liu, C., Pan, J., Liu, W. W., et al. (2013). KIF5B promotes the forward transport and axonal function of the voltage-gated sodium channel Nav1.8. Journal of Neuroscience, 33(45), 17884–17896.CrossRefPubMedGoogle Scholar
  55. Tasaka, G., Negishi, M., & Oinuma, I. (2012). Semaphorin 4D/Plexin-B1-mediated M-Ras GAP activity regulates actin-based dendrite remodeling through Lamellipodin. Journal of Neuroscience, 32(24), 8293–8305.CrossRefPubMedGoogle Scholar
  56. Thies, E., & Davenport, R. W. (2003). Independent roles of Rho-GTPases in growth cone and axonal behavior. Journal of Neurobiology, 54(2), 358–369.CrossRefPubMedGoogle Scholar
  57. Van Maldergem, L., Hou, Q., Kalscheuer, V. M., Rio, M., Doco-Fenzy, M., Medeira, A., et al. (2013). Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. Human Molecular Genetics, 22(16), 3306–3314.PubMedCentralCrossRefPubMedGoogle Scholar
  58. Villarroel-Campos, D., Gastaldi, L., Conde, C., Caceres, A., & Gonzalez-Billault, C. (2014). Rab-mediated trafficking role in neurite formation. Journal of Neurochemistry, 129(2), 240–248.CrossRefPubMedGoogle Scholar
  59. Volders, K., Nuytens, K., & Creemers, J. W. (2011). The autism candidate gene neurobeachin encodes a scaffolding protein implicated in membrane trafficking and signaling. Current Molecular Medicine, 11(3), 204–217.CrossRefPubMedGoogle Scholar
  60. Wang, S. Z., Ibrahim, L. A., Kim, Y. J., Gibson, D. A., Leung, H. C., Yuan, W., et al. (2013). Slit/Robo signaling mediates spatial positioning of spiral ganglion neurons during development of cochlear innervation. Journal of Neuroscience, 33(30), 12242–12254.PubMedCentralCrossRefPubMedGoogle Scholar
  61. Williams, E. L., & Casanova, M. F. (2011). Above genetics: lessons from cerebral development in autism. Translational Neuroscience, 2(2), 106–120.PubMedCentralCrossRefPubMedGoogle Scholar
  62. Wolff, J. J., & Piven, J. (2014). Neurodevelopmental disorders: Accelerating progress in autism through developmental research. Nature Reviews Neurology, 10(8), 431–432.CrossRefPubMedGoogle Scholar
  63. Ypsilanti, A. R., Zagar, Y., & Chédotal, A. (2010). Moving away from the midline: new developments for Slit and Robo. Development, 137(12), 1939–1952.CrossRefPubMedGoogle Scholar
  64. Zeidán-Chuliá, F., de Oliveira, B. H., Salmina, A. B., Casanova, M. F., Gelain, D. P., Noda, M., et al. (2014). Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: a model for disrupted brain connectome and therapy. Cell Death and Disease, 5, e1250.PubMedCentralCrossRefPubMedGoogle Scholar
  65. Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., et al. (2014). Deficient neuron–microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience, 17(3), 400–406.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jan Bakos
    • 1
    • 5
  • Zuzana Bacova
    • 1
    • 2
  • Stephen G. Grant
    • 3
  • Ana M. Castejon
    • 4
  • Daniela Ostatnikova
    • 5
  1. 1.Institute of Experimental EndocrinologySlovak Academy of SciencesBratislavaSlovakia
  2. 2.Department of Normal and Pathological Physiology, Faculty of MedicineSlovak Medical UniversityBratislavaSlovakia
  3. 3.College of Osteopathic MedicineNova Southeastern UniversityFort LauderdaleUSA
  4. 4.College of PharmacyNova Southeastern UniversityFort LauderdaleUSA
  5. 5.Faculty of Medicine, Institute of PhysiologyComenius UniversityBratislavaSlovakia

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