Effects of Toxicants on Neural Differentiation

  • Stanley BaroneJr.
  • Prasada R. S. Kodavanti
  • William R. Mundy
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Differentiation is a complex process by which a terminal cell phenotype is determined. During neural development, in vivo cells of the nervous system reach this terminal phenotype through both preprogrammed genetic signaling and epigenetic signaling. This genetic program can set up initial organizational planes and an initial temporal sequence of events, but epigenetic signals drive much of the later gene expression and subsequent protein expression that determines different phases of differentiation. This epigenetic signaling can stimulate pluripotent cells to become more restricted in their fate, usually leading to multipotent cells and eventually to a final terminal phenotype. Epigenetic signals include a number of morphogenic and neurotrophic molecules that determine phenotype based on (1) the level of exposure to these endogenous substances, (2) the order of exposure, and (3) the mixture of exposure to these different epigenetic signaling molecules. These complex signaling events are being elucidated with advances in stem cell research in which the signals that stimulate multipotent cells to become neurons, glia, muscle, or bone are starting to be revealed (1). Because of this complexity, it is difficult to tease these different signaling events apart in many in vivo systems and this is why a reductionist approach with in vitro systems is often favored.


PC12 Cell Nerve Growth Factor Neurite Outgrowth Primary Neuronal Culture NMDA Receptor Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Panchision, D. M. and McKay, R. D. (2002) The control of neural stem cells by morphogenic signals. Curr. Opin. Genet. Dev. 12, 478–487.PubMedCrossRefGoogle Scholar
  2. 2.
    Rice, D. C. and Barone, S. J. (2000) Critical Periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ. Health Perspect. 108(Suppl. 3), 511–533.PubMedCrossRefGoogle Scholar
  3. 3.
    Edenfeld, G., Pielage, J., and Klambt, C. (2002) Cell lineage specification in the nervous system. Curr. Opin. Genet. Dev. 12, 473–477.PubMedCrossRefGoogle Scholar
  4. 4.
    McConnell, S. K. (1990) The specification of neuronal identity in the mammalian cerebral cortex. Experientia 46, 922–929.PubMedCrossRefGoogle Scholar
  5. 5.
    Eagleson, K. L., Lillien, L., Chan, A. V., and Levitt, P. (1997) Mechanisms specifying area fate in cortex include cell-cycle-dependent decisions and the capacity of progenitors to express phenotype memory. Development 124, 1623–1630.PubMedGoogle Scholar
  6. 6.
    Greene, L. A. and Tischler, A. S. (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. USA 73, 2424–2428.PubMedCrossRefGoogle Scholar
  7. 7.
    Greene, L. A., Bernd, P., Black, M. M., et al. (1983) Genomic and non-genomic actions of nerve growth factor in development. Prog. Brain Res. 58, 347–357.PubMedCrossRefGoogle Scholar
  8. 8.
    Shaughnessy, L. W. and Barone, S. J. (1997) Damage to the NBM leads to a sustained lesion-induced increase in functional NGF in the cortex. NeuroReport 8, 2767–2774.PubMedCrossRefGoogle Scholar
  9. 9.
    Bosco, A. and Linden, R. (1999) BDNF and NT-4 differentially modulate neurite outgrowth in developing retinal ganglion cells. J. Neurosci. Res. 57, 759–769.PubMedCrossRefGoogle Scholar
  10. 10.
    Drubin, D. G., Feinstein, S. C., Shooter, E. M., and Kirschner, M. W. (1985) Nerve growth factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly-promoting factors. J. Cell Biol. 101, 1799–1807.PubMedCrossRefGoogle Scholar
  11. 11.
    Das, K. D. and Barone, S. J. (1999) Neuronal differentiation in PC12 cells is inhibited by chlorpyrifos and its metabolites: is acetylcholinesterase inhibition the site of action? Toxicol. Appl. Pharmacol. 160, 217–230.PubMedCrossRefGoogle Scholar
  12. 12.
    Crumpton, T. L., Atkins, D., Zawia, N., and Barone, S., Jr. (2001) Lead exposure in pheochromocytoma (PC12) cells alters neural differentiation and Sp1 DNA-binding. Neurotoxicology 22, 49–62.PubMedCrossRefGoogle Scholar
  13. 13.
    Parran, D. K., Mundy, W. R., and Barone, S. J. (2001) Effects of methylmercury and mercuric chloride on differentiation and cell viability in PC12 cells. Toxicol. Sci. 59, 278–290.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith, S. L., Sadler, C. J., Dodd, C. C., et al. (2001) The role of glutathione in the neurotoxicity of artemisinin derivatives in vitro. Biochem. Pharmacol. 61, 409–416.PubMedCrossRefGoogle Scholar
  15. 15.
    Brat, D. J. and Brimijoin, S. (1992) A paradigm for examining toxicant effects on viability, structure, and axonal transport of neurons in culture. Mol. Neurobiol. 6, 125–135.PubMedCrossRefGoogle Scholar
  16. 16.
    Audesirk, T. and Cabell, L. (1999) Nanomolar concentrations of nicotine and cotinine alter the development of cultured hippocampal neurons via non-acetylcholine receptor-mediated mechanisms. Neurotoxicology 20, 639–646.PubMedGoogle Scholar
  17. 17.
    Mariussen, E., Myhre, O., Reistad, T., and Fonnum, F. (2002) The polychlorinated biphenyl mixture aroclor 1254 induces death of rat cerebellar granule cells: the involvement of the N-methyl-d-aspartate receptor and reactive oxygen species. Toxicol. Appl. Pharmacol. 179, 137–144.PubMedCrossRefGoogle Scholar
  18. 18.
    Layer, P. G. (1991) Cholinesterases during development of the avian nervous system. Cell Mol. Neurobiol. 11, 7–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Layer, P. G., Weikert, T., and Alber, R. (1993) Cholinesterases regulate neurite growth of chick nerve cells in vitro by means of a non-enzymatic mechanism. Cell Tissue Res. 273, 219–226.PubMedCrossRefGoogle Scholar
  20. 20.
    Bywood, P. T. and Johnson, S. M. (2000) Dendrite loss is a characteristic early indicator of toxin-induced neurodegeneration in rat midbrain slices. Exp. Neurol. 161, 306–316.PubMedCrossRefGoogle Scholar
  21. 21.
    Lotto, R. B. and Price, D. J. (1996) Effects of subcortical structures on the growth of cortical neurites in vitro. NeuroReport 7, 1185–1188.PubMedCrossRefGoogle Scholar
  22. 22.
    Bilsland, J., Rigby, M., Young, L., and Harper, S. (1999) A rapid method for semi-quantitative analysis of neurite outgrowth from chick DRG explants using image analysis. J. Neurosci. Methods 92, 75–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Audesirk, G. and Audesirk, T. (1998) Neurite development, in Handbook of Developmental Neurotoxicology (Slikker, W. J. and Chang, L. W., eds.), Academic, San Diego, pp. 61–86.CrossRefGoogle Scholar
  24. 24.
    Cory-Slechta, D. A. (1995) Relationships between lead-induced learning impairments and changes in dopaminerigic, cholinerigic, and glutamatergic neurotransmitter system functions. Annu. Rev. Pharmacol. Toxicol. 35, 391–415.PubMedCrossRefGoogle Scholar
  25. 25.
    Lasley, S. M. and Lane, J. D. (1988). Diminished regulation of mesolimbic dopaminergic activity in rat after chronic inorganic lead exposure. Toxicol. Appl. Pharmacol. 95, 474–483.PubMedCrossRefGoogle Scholar
  26. 26.
    Lasley, S. M., Greenland, R. D., Minnema, D. J., and Michaelson, I. A. (1984) Influence of chronic inorganic lead exposure on regional dopamine and 5-HT turnover in rat brain. Neurochem. Res. 9, 1675–1688.PubMedCrossRefGoogle Scholar
  27. 27.
    Moreira, E. G., Vassilieff, V. S., Vassilieff, I., et al. (2002) Developmental lead exposure: neurochemical and neuroanatomical effects in the rat. Toxicologist 66, 125.Google Scholar
  28. 28.
    Parran, D. K., Barone, S., Jr., and Mundy, W. R. (2003) Methylmercury inhibits NGF-induced TrkA autophosphorylation and neurite outgrowth in PC12 cells. Dev. Brain Res. 141(1–2), 71–81.CrossRefGoogle Scholar
  29. 29.
    Graff, R. D., Falconer, M. M., Brown, D. L., and Reuhl, K. R. (1997) Altered sensitivity of posttranslationally modified microtubules to methylmercury in differentiating embryonal carcinoma-derived neurons. Toxicol. Appl. Pharmacol. 144, 215–224.PubMedCrossRefGoogle Scholar
  30. 30.
    Lagunowich, L. A., Bhambhani, S., Graff, R. D., and Reuhl, K. (1991) Cell adhesion molecules in the cerebellum: Targets of methylmercury toxicity? Soc. Neurosci. 17, 515.Google Scholar
  31. 31.
    Dey, P. M., Gochfeld, M., and Reuhl, K. R. (1999) Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity. Brain Res. 845, 139–151.PubMedCrossRefGoogle Scholar
  32. 32.
    Barone, S. J., Haykal-Coates, N., Parran, D. K., and Tilson, H. A. (1998) Gestational exposure to methylmercury alters the developmental pattern of trk-like immunoreactivity in the rat brain and results in cortical dysmorphology. Dev. Brain Res. 109, 13–31.CrossRefGoogle Scholar
  33. 33.
    Honegger, P. (1985) Biochemical differentiation in serum-free aggregating brain cell cultures, in Cell Culture in the Neurosciences (Bottenstein, J. E. and Sato, G., eds.), Plenum, New York, pp. 223–243.Google Scholar
  34. 34.
    Guroff, G. (1985) PC12 cells as a model of neuronal differentiation, in Cell Culture in the Neurosciences (Bottenstein, J. and Sato, G., eds.), Plenum, New York, pp. 245–272.Google Scholar
  35. 35.
    O’Callaghan, J. P. (1988) Neurotypic and gliotypic proteins as biochemical markers of neurotoxicity. Neurotoxicol. Teratol. 10, 445–452.CrossRefGoogle Scholar
  36. 36.
    O’Callaghan, J. P. and Miller, D. B. (1989) Assessment of chemically-induced alterations in brain development using assays of neuron-and glia-localized proteins. Neurotoxicology 10, 393–406.Google Scholar
  37. 37.
    Reinhardt, C. A. (1993) Neurodevelopmental toxicity in vitro: primary cell culture models for screening and risk assessment. Reprod. Toxicol. 7(Suppl. 1), 165–170.PubMedCrossRefGoogle Scholar
  38. 38.
    Abdulla, E. M. and Campbell, I. C. (1993) l-BMAA and kainate-induced modulation of neurofilament concentrations as a measure of neurite outgrowth: implications for an in vitro test of neurotoxicity. Toxicol. In Vitro 7, 341–344.PubMedCrossRefGoogle Scholar
  39. 39.
    Garrels, J. I. and Schubert, D. (1979) Modulation of protein synthesis by nerve growth factor. J. Biol. Chem. 254, 7978–7985.PubMedGoogle Scholar
  40. 40.
    McGuire, J. C., Greene, L. A., and Furano, A. V. (1978) NGF stimulates incorporation of fucose or glucosamine into an external glycoprotein in cultured rat PC12 pheochromocytoma cells. Cell 15, 357–365.PubMedCrossRefGoogle Scholar
  41. 41.
    McGuire, J. C. and Greene, L. A. (1980) Stimulation by nerve growth factor of specific protein synthesis in rat PC12 pheochromocytoma cells. Neuroscience 5, 179–189.PubMedCrossRefGoogle Scholar
  42. 42.
    Goslin, K. and Banker, G. (1989) Experimental observations on the development of polarity by hippocampal neurons in culture. J. Cell Biol. 108, 1507–1516.PubMedCrossRefGoogle Scholar
  43. 43.
    Greene, L. A. and Rein, G. (1977) Synthesis, storage and release of acetylcho-line by a noradrenergic pheochromocytoma cell line. Nature 268, 349–351.PubMedCrossRefGoogle Scholar
  44. 44.
    Edgar, D. H. and Thoenen, H. (1978) Selective enzyme induction in a nerve growth factor-responsive pheochromocytoma cell line (PC 12). Brain Res. 154, 186–190.PubMedCrossRefGoogle Scholar
  45. 45.
    Lucas, C. A., Czlonkowska, A., and Kreutzberg, G. W. (1980) Regulation of acetylcholinesterase by nerve growth factor in the pheochromocytoma PC12 cell line. Neurosci. Lett. 18, 333–337.PubMedCrossRefGoogle Scholar
  46. 46.
    Rieger, F., Shelanski, M. L., and Greene, L. A. (1980) The effects of nerve growth factor on acetylcholinesterase and its multiple forms in cultures of rat PC12 pheochromocytoma cells: increased total specific activity and appearance of the 16 S molecular form. Dev. Biol. 76, 238–243.PubMedCrossRefGoogle Scholar
  47. 47.
    Greene, L. A. and Rukenstein, A. (1981) Regulation of acetylcholinesterase activity by nerve growth factor. Role of transcription and dissociation from effects on proliferation and neurite outgrowth. J. Biol. Chem. 256, 6363–6367.PubMedGoogle Scholar
  48. 48.
    Hatanaka, H. (1981) Nerve growth factor-mediated stimulation of tyrosine hydroxylase activity in a clonal rat pheochromocytoma cell line. Brain Res. 222, 225–233.PubMedCrossRefGoogle Scholar
  49. 49.
    Layer, P. G. and Willbold, E. (1995) Novel functions of cholinesterases in development, physiology and disease. Prog. Histochem. Cytochem. 29, 1–94.PubMedGoogle Scholar
  50. 50.
    Bigbee, J. W., Sharma, K. V., Gupta, J. J., and Dupree, J. L. (1999) Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development. Environ. Health Perspect. 107(Suppl. 1), 81–87.PubMedCrossRefGoogle Scholar
  51. 51.
    Caceres, A., Banker, G., Steward, O., Binder, L., and Payne, M. (1984) MAP2 is localized to the dendrites of hippocampal neurons which develop in culture. Brain Res. 315, 314–318.PubMedGoogle Scholar
  52. 52.
    Dupree, J. L. and Bigbee, J. W. (1994) Retardation of neuritic outgrowth and cytoskeletal changes accompany acetylcholinesterase inhibitor treatment in cultured rat dorsal root ganglion neurons. J. Neurosci. Res. 39, 567–575.PubMedCrossRefGoogle Scholar
  53. 53.
    Sharma, K. V. and Bigbee, J. W. (1998) Acetylcholinesterase antibody treatment results in neurite detachment and reduced outgrowth from cultured neurons: further evidence for a cell adhesive role for neuronal acetylcholinesterase. J. Neurosci. Res. 53, 454–464.PubMedCrossRefGoogle Scholar
  54. 54.
    Dichter, M. A., Tischler, A. S., and Greene, L. A. (1977) Nerve growth factor-induced increase in electrical excitability and acetylcholine sensitivity of a rat pheochromocytoma cell line. Nature 268, 501–504.PubMedCrossRefGoogle Scholar
  55. 55.
    Ifune, C. K. and Steinbach, J. H. (1990) Regulation of sodium currents and acetylcholine responses in PC12 cells. Brain Res. 506, 243–248.PubMedCrossRefGoogle Scholar
  56. 56.
    Boyd, N. D. (1987) Two distinct kinetic phases of desensitization of acetylcholine receptors of clonal rat PC12 cells. J. Physiol. 389, 45–67.PubMedGoogle Scholar
  57. 57.
    Whiting, P. J., Schoepfer, R., Swanson, L. W., Simmons, D. M., and Lindstrom, J. M. (1987) Functional acetylcholine receptor in PC12 cells reacts with a monoclonal antibody to brain nicotinic receptors. Nature 327, 515–518.PubMedCrossRefGoogle Scholar
  58. 58.
    Jumblatt, J. E. and Tischler, A. S. (1982) Regulation of muscarinic ligand binding sites by nerve growth factor in PC12 phaeochromocytoma cells. Nature 297, 152–154.PubMedCrossRefGoogle Scholar
  59. 59.
    Cross, A. J., Johnson, J. A., Frith, C., and Taylor, G. R. (1984) Muscarinic cholinergic receptors in a rat pheochromocytoma cell line. Biochem. Biophys. Res. Commun. 119, 163–167.PubMedCrossRefGoogle Scholar
  60. 60.
    Viana, G. B., Davis, L. H., and Kauffman, F. C. (1988) Effects of organophosphates and nerve growth factor on muscarinic receptor binding number in rat pheochromocytoma PC12 cells. Toxicol. Appl. Pharmacol. 93, 257–266.PubMedCrossRefGoogle Scholar
  61. 61.
    McDonald, J. W., Johnston, M. V., and Young, A. B. (1990) Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus. Exp. Neurol. 110, 237–247.PubMedCrossRefGoogle Scholar
  62. 62.
    Ishii, T., Moriyoshi, K., Sugihara, H., et al. (1993) Molecular characterization of the family of the N-methyl-d-aspartate receptor subunits. J. Biol. Chem. 268, 2836–2843.PubMedGoogle Scholar
  63. 63.
    Monyer, H., Sprengel, R., Schoepfer, R., et al. (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256, 1217–1221.PubMedCrossRefGoogle Scholar
  64. 64.
    Williams, K., Russell, S. L., Shen, Y. M., and Molinoff, P. B. (1993) Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron 10, 267–278.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhong, J., Russell, S. L., Pritchett, D. B., Molinoff, P. B., and Williams, K. (1994) Expression of mRNAs encoding subunits of the N-methyl-D-aspartate receptor in cultured cortical neurons. Mol. Pharmacol. 45, 846–853.PubMedGoogle Scholar
  66. 66.
    Mizuta, I., Katayama, M., Watanabe, M., Mishina, M., and Ishii, K. (1998) Developmental expression of NMDA receptor subunits and the emergence of glutamate neurotoxicity in primary cultures of murine cerebral cortical neurons. Cell. Mol. Life Sci. 54, 721–725.PubMedCrossRefGoogle Scholar
  67. 67.
    Cheng, C., Fass, D. M., and Reynolds, I. J. (1999) Emergence of excitotoxicity in cultured forebrain neurons coincides with larger glutamate-stimulated [Ca(2+)](i) increases and NMDA receptor mRNA levels. Brain Res. 849, 97–108.PubMedCrossRefGoogle Scholar
  68. 68.
    Rudy, B., Kirschenbaum, B., Rukenstein, A., and Greene, L. A. (1987) Nerve growth factor increases the number of functional Na channels and induces TTX-resistant Na channels in PC12 pheochromocytoma cells. J. Neurosci. 7, 1613–1625.PubMedGoogle Scholar
  69. 69.
    Nowycky, M. C., Fox, A. P., and Tsien, R. W. (1985) Three types of neuronal calcium channels with different calcium agonist sensitivity. Nature 316, 440–443.PubMedCrossRefGoogle Scholar
  70. 70.
    Tsien, R. W., Lipscombe, D., Madison, D. V., Bley, K. R., and Fox, A. P. (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci. 11, 431–438.PubMedCrossRefGoogle Scholar
  71. 71.
    Takahashi, T. and Momiyama, A. (1993) Different types of calcium channels mediate central synaptic transmission. Nature 366, 156–158.PubMedCrossRefGoogle Scholar
  72. 72.
    Wheeler, D. B., Randall, A., and Tsien, R. W. (1994) Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111.PubMedCrossRefGoogle Scholar
  73. 73.
    Shafer, T. J. and Atchison, W. D. (1991) Methylmercury blocks N-and L-type Ca++ channels in nerve growth factor-differentiated pheochromocytoma (PC12) cells. J. Pharmacol. Exp. Ther. 258, 149–157.PubMedGoogle Scholar
  74. 74.
    Streit, J. and Lux, H. D. (1987) Voltage dependent calcium currents in PC12 growth cones and cells during NGF-induced cell growth. Pflugers Arch. 408, 634–641.PubMedCrossRefGoogle Scholar
  75. 75.
    Plummer, M. R., Logothetis, D. E., and Hess, P. (1989) Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 2, 1453–1463.PubMedCrossRefGoogle Scholar
  76. 76.
    Usowicz, M. M., Porzig, H., Becker, C., and Reuter, H. (1990) Differential expression by nerve growth factor of two types of Ca2+ channels in rat pheochromocytoma cell lines. J. Physiol. 426, 95–116.PubMedGoogle Scholar
  77. 77.
    Furukawa, K., Onodera, H., Kogure, K., and Akaike, N. (1993) Time-dependent expression of Na and Ca channels in PC12 cells by nerve growth factor and cAMP. Neurosci. Res. 16, 143–147.PubMedCrossRefGoogle Scholar
  78. 78.
    Lewis, D. L., De Aizpurua, H. J., and Rausch, D. M. (1993) Enhanced expression of Ca2+ channels by nerve growth factor and the v-src oncogene in rat pheochromocytoma cells. J. Physiol. 465, 325–342.PubMedGoogle Scholar
  79. 79.
    Bouron, A., Becker, C., and Porzig, H. (1999) Functional expression of voltagegated Na+ and Ca2+ channels during neuronal differentiation of PC12 cells with nerve growth factor or forskolin. Naunyn Schmiedebergs Arch. Pharmacol. 359, 370–377.PubMedCrossRefGoogle Scholar
  80. 80.
    Shafer, T. J., Meacham, C. A., and Barone, S. (2002) Effects of prolonged exposure to nanomolar concentrations of methylmercury on voltage-sensitive sodium and calcium currents in PC12 cells. Dev. Brain Res. 136, 151–164.CrossRefGoogle Scholar
  81. 81.
    Porter, N. M., Thibault, O., Thibault, V., Chen, K. C., and Landfield, P. W. (1997) Calcium channel density and hippocampal cell death with age in long-term culture. J. Neurosci. 17, 5629–5639.PubMedGoogle Scholar
  82. 82.
    Blalock, E. M., Porter, N. M., and Landfield, P. W. (1999) Decreased G-protein-mediated regulation and shift in calcium channel types with age in hippocampal cultures. J. Neurosci. 19, 8674–8684.PubMedGoogle Scholar
  83. 83.
    Abdulla, E. M., Calaminici, M., and Campbell, I. C. (1995) Comparison of neurite outgrowth with neurofilament protein subunit levels in neuroblastoma cells following mercuric oxide exposure. Clin. Exp. Pharmacol. Physiol. 22, 362–363.PubMedCrossRefGoogle Scholar
  84. 84.
    Clarkson, T. W., Sager, P. R., and Syversen, T. L. (1986) The Cytoskeleton. A Target for Toxic Agents, Plenum, New York.Google Scholar
  85. 85.
    Nunez, J. (1986) Differential expression of microtubule components during brain development. Dev. Neurosci. 8, 125–141.PubMedCrossRefGoogle Scholar
  86. 86.
    Matus, A., Bernhardt, R., Bodmer, R., and Alaimo, D. (1986) Microtubule-associated protein 2 and tubulin are differently distributed in the dendrites of developing neurons. Neuroscience 17, 371–389.PubMedCrossRefGoogle Scholar
  87. 87.
    Kobayashi, N. and Mundel, P. (1998) A role of microtubules during the formation of cell processes in neuronal and non-neuronal cells. Cell Tissue Res. 291, 163–174.PubMedCrossRefGoogle Scholar
  88. 88.
    Brugg, B. and Matus, A. (1988) PC12 cells express juvenile microtubule-associated proteins during nerve growth factor-induced neurite outgrowth. J. Cell Biol. 107, 643–650.PubMedCrossRefGoogle Scholar
  89. 89.
    Greene, L. A., Liem, R. K., and Shelanski, M. L. (1983) Regulation of a high molecular weight microtubule-associated protein in PC12 cells by nerve growth factor. J. Cell Biol. 96, 76–83.PubMedCrossRefGoogle Scholar
  90. 90.
    Caceres, A., Banker, G. A., and Binder, L. (1986) Immunocytochemical localization of tubulin and microtubule-associated protein 2 during the development of hippocampal neurons in culture. J. Neurosci. 6, 714–722.PubMedGoogle Scholar
  91. 91.
    Fletcher, T. L., De Camilli, P., and Banker, G. (1994) Synaptogenesis in hippocampal cultures: evidence indicating that axons and dendrites become competent to form synapses at different stages of neuronal development. J. Neurosci. 14, 6695–6706.PubMedGoogle Scholar
  92. 92.
    Guo, X., Chandrasekaran, V., Lein, P., Kaplan, P. L., and Higgins, D. (1999) Leukemia inhibitory factor and ciliary neurotrophic factor cause dendritic retraction in cultured rat sympathetic neurons. J. Neurosci. 19, 2113–2121.PubMedGoogle Scholar
  93. 93.
    Sager, P. R. and Matheson, D. W. (1988) Mechanisms of neurotoxicity related to selective disruption of microtubules and intermediate filaments. Toxicology 49, 479–492.PubMedCrossRefGoogle Scholar
  94. 94.
    Hunter, A. M. and Brown, D. L. (2000) Effects of microtubule-associated protein (MAP) expression on methylmercury-induced microtubule disassembly. Toxicol. Appl. Pharmacol. 166, 203–213.PubMedCrossRefGoogle Scholar
  95. 95.
    Rosso, S. B., Caceres, A. O., de Duffard, A. M., Duffard, R. O., and Quiroga, S. (2000) 2,4-Dichlorophenoxyacetic acid disrupts the cytoskeleton and disorganizes the Golgi apparatus of cultured neurons. Toxicol. Sci. 56, 133–140.PubMedCrossRefGoogle Scholar
  96. 96.
    Choudhary, S., Joshi, K., and Gill, K. D. (2001) Possible role of enhanced microtubule phosphorylation in dichlorvos induced delayed neurotoxicity in rat. Brain Res. 897, 60–70.PubMedCrossRefGoogle Scholar
  97. 97.
    Paglini, G., Peris, L., Mascotti, F., Quiroga, S., and Caceres, A. (2000) Tau protein function in axonal formation. Neurochem. Res. 25, 37–42.PubMedCrossRefGoogle Scholar
  98. 98.
    Dotti, C. G., Banker, G. A., and Binder, L. I. (1987) The expression and distribution of the microtubule-associated proteins tau and microtubule-associated protein 2 in hippocampal neurons in the rat in situ and in cell culture. Neuroscience 23, 121–130.PubMedCrossRefGoogle Scholar
  99. 99.
    Litman, P., Barg, J., Rindzoonski, L., and Ginzburg, I. (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: implications for neuronal polarity. Neuron 10, 627–638.PubMedCrossRefGoogle Scholar
  100. 100.
    Rasouly, D., Rahamim, E., Ringel, I., et al. (1994) Neurites induced by staurosporine in PC12 cells are resistant to colchicine and express high levels of tau proteins. Mol. Pharmacol. 45, 29–35.PubMedGoogle Scholar
  101. 101.
    Smith, C. J., Anderton, B. H., Davis, D. R., and Gallo, J. M. (1995) Tau isoform expression and phosphorylation state during differentiation of cultured neuronal cells. FEBS Lett. 375, 243–248.PubMedCrossRefGoogle Scholar
  102. 102.
    Benowitz, L. I. and Routtenberg, A. (1997) GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20, 84–91.PubMedCrossRefGoogle Scholar
  103. 103.
    Perrone-Bizzozero, N. I., Finklestein, S. P., and Benowitz, L. I. (1986) Synthesis of a growth-associated protein by embryonic rat cerebrocortical neurons in vitro. J. Neurosci. 6, 3721–3730.PubMedGoogle Scholar
  104. 104.
    Meiri, K. F., Willard, M., and Johnson, M. I. (1988) Distribution and phosphorylation of the growth-associated protein GAP-43 in regenerating sympathetic neurons in culture. J. Neurosci. 8, 2571–2581.PubMedGoogle Scholar
  105. 105.
    Costello, B., Meymandi, A., and Freeman, J. A. (1990) Factors influencing GAP-43 gene expression in PC12 pheochromocytoma cells. J. Neurosci. 10, 1398–1406.PubMedGoogle Scholar
  106. 106.
    Dani, J. W., Armstrong, D. M., and Benowitz, L. I. (1991) Mapping the development of the rat brain by GAP-43 immunocytochemistry. Neuroscience 40, 277–287.PubMedCrossRefGoogle Scholar
  107. 107.
    McGuire, C. B., Snipes, G. J., and Norden, J. J. (1988) Light-microscopic immunolocalization of the growth-and plasticity-associated protein GAP-43 in the developing rat brain. Brain Res. 469, 277–291.PubMedGoogle Scholar
  108. 108.
    Goslin, K., Schreyer, D. J., Skene, J. H., and Banker, G. (1990) Changes in the distribution of GAP-43 during the development of neuronal polarity. J. Neurosci. 10, 588–602.PubMedGoogle Scholar
  109. 109.
    Jap Tjoen, S. E., Schmidt-Michels, M. H., Spruijt, B. M., Oestreicher, A. B., Schotman, P., and Gispen, W. H. (1991) Quantitation of the growth-associated protein B-50/GAP-43 and neurite outgrowth in PC12 cells. J. Neurosci. Res. 29, 149–154.Google Scholar
  110. 110.
    Jap Tjoen, S. E., Schmidt-Michels, M., Oestreicher, A. B., Schotman, P., and Gispen, W. H. (1992) Dexamethasone-induced effects on B-50/GAP-43 expression and neurite outgrowth in PC12 cells. J. Mol. Neurosci. 3, 189–195.Google Scholar
  111. 111.
    Das, K. P., Freudenrich, T. M., and Mundy, W. R. (2001) Evaluation of protein markers for neuronal differentiation in PC12 cells. Toxicologist 61, 373.Google Scholar
  112. 112.
    Przyborski, S. A. and Cambray-Deakin, M. A. (1994) Developmental changes in GAP-43 expression in primary cultures of rat cerebellar granule cells. Mol. Brain Res. 25, 273–285.PubMedCrossRefGoogle Scholar
  113. 113.
    Thiel, G. (1993) Synapsin I, synapsin II, and synaptophysin: marker proteins of synaptic vesicles. Brain Pathol. 3, 87–95.PubMedCrossRefGoogle Scholar
  114. 114.
    Knaus, P., Betz, H., and Rehm, H. (1986) Expression of synaptophysin during postnatal development of the mouse brain. J. Neurochem. 47, 1302–1304.PubMedCrossRefGoogle Scholar
  115. 115.
    Romano, C., Nichols, R. A., Greengard, P., and Greene, L. A. (1987) Synapsin I in PC12 cells. I. Characterization of the phosphoprotein and effect of chronic NGF treatment. J. Neurosci. 7, 1294–1299.PubMedGoogle Scholar
  116. 116.
    Ferreira, A., Kao, H. T., Feng, J., Rapoport, M., and Greengard, P. (2000) Synapsin III: developmental expression, subcellular localization, and role in axon formation. J. Neurosci. 20, 3736–3744.PubMedGoogle Scholar
  117. 117.
    Ehrhart-Bornstein, M., Treiman, M., Hansen, G. H., Schousboe, A., Thorn, N. A., and Frandsen, A. (1991) Parallel expression of synaptophysin and evoked neurotransmitter release during development of cultured neurons. Int. J. Dev. Neurosci. 9, 463–471.PubMedCrossRefGoogle Scholar
  118. 118.
    George, J. M. (2002) The synucleins. Genome Biol. 3, REVIEWS3002.Google Scholar
  119. 119.
    Withers, G. S., George, J. M., Banker, G. A., and Clayton, D. F. (1997) Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Dev. Brain Res. 99, 87–94.CrossRefGoogle Scholar
  120. 120.
    George, J. M., Jin, H., Woods, W. S., and Clayton, D. F. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361–372.PubMedCrossRefGoogle Scholar
  121. 121.
    Maroteaux, L. and Scheller, R. H. (1991) The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Mol. Brain Res. 11, 335–343.PubMedCrossRefGoogle Scholar
  122. 122.
    Shibayama-Imazu, T., Okahashi, I., Omata, K., et al. (1993) Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14). Brain Res. 622, 17–25.PubMedCrossRefGoogle Scholar
  123. 123.
    Hsu, L. J., Mallory, M., Xia, Y., et al. (1998) Expression pattern of synucleins (non-Abeta component of Alzheimer’s disease amyloid precursor protein/alpha-synuclein) during murine brain development. J. Neurochem. 71, 338–344.PubMedCrossRefGoogle Scholar
  124. 124.
    Stefanis, L., Kholodilov, N., Rideout, H. J., Burke, R. E., and Greene, L. A. (2001) Synuclein-1 is selectively up-regulated in response to nerve growth factor treatment in PC12 cells. J. Neurochem. 76, 1165–1176.PubMedCrossRefGoogle Scholar
  125. 125.
    Pollerberg, G. E., Burridge, K., Krebs, K. E., Goodman, S. R., and Schachner, M. (1987) The 180-kD component of the neural cell adhesion molecule N-CAM is involved in a cell-cell contacts and cytoskeleton-membrane interactions. Cell Tissue Res. 250, 227–236.PubMedCrossRefGoogle Scholar
  126. 126.
    Edelman, G. M. (1986) Cell adhesion molecules in the regulation of animal form and tissue pattern. Annu. Rev. Cell Biol. 2, 81–116.PubMedCrossRefGoogle Scholar
  127. 127.
    Brackenbury, R., Sorkin, B. C., and Cunningham, B. A. (1987) Molecular features of cell adhesion molecules involved in neural development. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 65, 155–167.PubMedGoogle Scholar
  128. 128.
    Cookman, G. R., King, W., and Regan, C. M. (1987) Chronic low-level lead exposure impairs embryonic to adult conversion of the neural cell adhesion molecule. J. Neurochem. 49, 399–403.PubMedCrossRefGoogle Scholar
  129. 129.
    Regan, C. M. (1993) Neural cell adhesion molecules, neuronal development and lead toxicity. Neurotoxicology 14, 69–74.PubMedGoogle Scholar
  130. 130.
    Reuhl, K. R., Rice, D. C., Gilbert, S. G., and Mallett, J. (1989) Effects of chronic developmental lead exposure on monkey neuroanatomy: visual system. Toxicol. Appl. Pharmacol. 99, 501–509.PubMedCrossRefGoogle Scholar
  131. 131.
    Pyle, S. J. and Reuhl, K. R. (1997) Cytoskeletal elements in neurotoxicity, in Nervous System and Behavioral Toxicology (Lowndes, H. E. and Reuhl, K. R., eds.), Elsevier, New York, Vol. II, pp. 79–97.Google Scholar
  132. 132.
    Zurmohle, U. M., Herms, J., Schlingensiepen, R., Schlingensiepen, K. H., and Brysch, W. (1994) Changes of synapsin I messenger RNA expression during rat brain development. Exp. Brain Res. 99, 17–24.PubMedCrossRefGoogle Scholar
  133. 133.
    Tcherepanov, A. A. and Sokolov, B. P. (1997) Age-related abnormalities in expression of mRNAs encoding synapsin 1A, synapsin 1B, and synaptophysin in the temporal cortex of schizophrenics. J. Neurosci. Res. 49, 639–644.PubMedCrossRefGoogle Scholar
  134. 134.
    Curtis, R., Green, D., Lindsay, R. M., and Wilkin, G. P. (1993) Up-regulation of GAP-43 and growth of axons in rat spinal cord after compression injury. J. Neurocytol. 22, 51–64.PubMedCrossRefGoogle Scholar
  135. 135.
    Schmitt, T. J., Zawia, N., and Harry, G. J. (1996) GAP-43 mRNA expression in the developing rat brain: alterations following lead-acetate exposure. Neurotoxicology 17, 407–414.PubMedGoogle Scholar
  136. 136.
    Zawia, N. H. and Harry, G. J. (1996) Developmental exposure to lead interferes with glial and neuronal differential gene expression in the rat cerebellum. Toxicol. Appl. Pharmacol. 138, 43–47.PubMedCrossRefGoogle Scholar
  137. 137.
    Ginzburg, I., Scherson, T., Giveon, D., Behar, L., and Littauer, U. Z. (1982) Modulation of mRNA for microtubule-associated proteins during brain development. Proc. Natl. Acad. Sci. USA 79, 4892–4896.PubMedCrossRefGoogle Scholar
  138. 138.
    Thomas, P. S. (1980) Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc. Natl. Acad. Sci. USA 77, 5201–5205.PubMedCrossRefGoogle Scholar
  139. 139.
    Berk, A. J. and Sharp, P. A. (1977) Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell 12, 721–732.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2004

Authors and Affiliations

  • Stanley BaroneJr.
    • 1
  • Prasada R. S. Kodavanti
    • 2
  • William R. Mundy
    • 2
  1. 1.Cellular and Molecular Toxicology BranchNeurotoxicology Division/NHEERL/ORD US Environmental Protection AgencyResearch Triangle Park
  2. 2.Neurotoxicology DivisionUS Environmental Protection AgencyResearch Triangle Park

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