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Gonadal steroid enhancement of facial nerve regeneration: Role of heat shock protein 70

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Journal of Neurocytology

Abstract

Over the past decade, our laboratory has been investigating the now well-established neurotrophic capabilities of gonadal steroids in the context of peripheral nerve injury and repair. The focus of our work has been on the hamster facial motoneuron (FMN) system (Kujawa & Jones, 1995), although we have recently begun to explore two additional motoneuron injury paradigms, the rat sciatic and hamster rubrospinal systems (Kujawa et al., 1993). In this brief review, we will discuss the effects of androgens and estrogens on the regenerative properties and the molecular programming of injured hamster FMN. This will be followed by a discussion of the effects of androgens on the glial response to injury in the facial nucleus. Finally, a working model of the mechanism by which gonadal steroids enhance neuronal reparative processes will be advanced. Our proposed mechanism involves a neuroprotective role for gonadal steroids, in that we hypothesize that exposure to these agents at the time of injury reduces the need for the injured neuron to mount a classical “stress response” involving the production of heat shock protein 70. Finally, a series of future directions for our work will be presented.

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References

  • BEAUCAMP, N., HARDING, T. C., GEDDES, B. J., WILLIAMS, J. & UNEY, J. B. (1998) Overexpression of hsp 79i facilitates reactivation of intracellular proteins in neurones and protects them from denaturing stress. FEBS Letters 441, 215–219.

    PubMed  Google Scholar 

  • BISBY, M. A. (1985) Enhancement of the conditioning lesion effect in rat sciatic motor axons after superimposition of conditioning and test lesions. Experimental Neurology 90, 385–394.

    PubMed  Google Scholar 

  • BLINZINGER, K. & KREUTZBERG, G. (1968) Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Zeitschrift fur Zellforschung und mikroskopische Anatomie 85, 145–157.

    PubMed  Google Scholar 

  • BROWN, I. R. & LOWE, D. G. (1985) Expression of heat shock genes in fetal and maternal rabbit brain. Biochemical Research 10, 1277–1284.

    Google Scholar 

  • CHAI, U., KOPPENHAFER, S. L., BONINI, N. M. & PAULSON, H. L. (1999) Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. Journal of Neuroscience 19, 10338–10347.

    PubMed  Google Scholar 

  • CHEN, D. H., CHAMBERS, W. W. & LIU, C. N. (1977) Synaptic displacement in intracentral neurons of Clarkés nucleus following axotomy in the cat. Experimental Neurology 57, 1026–1041.

    PubMed  Google Scholar 

  • CLARK, P., JONES, K. J. & LAVELLE, A. (1991) Ultrastructural changes in the nucleolus of facial motor neurons following axotomy during an early critical period in development. Journal of Comparative Neurology 312, 123–144.

    Google Scholar 

  • COHEN, R. S. & PFAFF, D. W. (1981) Ultrastructure of neurons in the ventromedial nucleus of the hypothalamus in ovariectomized rats with or without estrogen treatment. Cell and Tissue Research 217, 451–470.

    PubMed  Google Scholar 

  • DRENGLER, S. M., HANDA, R. J. & JONES, K. J. (1996a) Regulation of androgen receptor mRNA expression in hamster facial motoneurons: Differential effects of nonaromatizable and aromatizable androgens. Molecular Brain Research 41, 8–15.

    PubMed  Google Scholar 

  • DRENGLER, S. M., HANDA, R. J. & JONES, K. J. (1996b) Sex differences in androgen receptor mRNA levels and regulation in hamster facial motoneurons. Molecular Brain Research 35, 131–138.

    PubMed  Google Scholar 

  • DRENGLER, S. M., HANDA, R. J. & JONES, K. J. (1997) Effects of axotomy and testosterone on androgen receptor mRNA expression in hamster facial motoneurons. Experimental Neurology 146, 374–379.

    PubMed  Google Scholar 

  • ENG, L. F. (1988) Astrocytic response to injury. In Current Issues in Neural Regeneration Research(edited by REIER, P., BUNGE, R. & SEIL, F.). New York: Alan R. Liss.

    Google Scholar 

  • EVANS, R. M. (1988) The steroid and thyroid hormone receptor superfamily. Science 240, 889–895.

    Google Scholar 

  • FORMAN, D. S. & BERENBERG, R. A. (1978) Regeneration of motor axons in the rat sciatic nerve studied by labeling with axonally transported radioactive proteins. Brain Research 156, 213–225.

    PubMed  Google Scholar 

  • GARCIA-ESTRADA, J., DELRIO, J. A., LUQUIN, S., SORIANO, E. & GARCIA-SEGURA, L. M. (1993) Gonadal hormones down-regulate reactive gliosis and astrocyte proliferation after a penetrating brain injury. Brain Research 628, 271–278.

    PubMed  Google Scholar 

  • GARCIA-SEGURA, L. M., TORRES-ALEMAN, I. & NAFTOLIN, F. (1989) Astrocytic shape and glial fibrillary acidic protein immunoreactivity are modified by estradiol in primary rat hypothalamic cultures. Brain Research 47, 298–302.

    Google Scholar 

  • GOLDSTEIN, L. A. & SENGELAUB, D. R. (1993) Motoneuron morphology in the dorsolateral nucleus of the rat spinal cord: Normal development and androgenic regulation. Journal of Comparative Neurology 338, 588–600.

    PubMed  Google Scholar 

  • GRAEBER, M. B. & KREUTZBERG, G. W. (1986) Astrocytes increase in glial fibrillary acidic protein during retrograde changes of facial motor neurons. Journal of Neurocytology 15, 363–373.

    PubMed  Google Scholar 

  • HADJIOLOV, A. A. (1985) The Nucleolus & Ribosome Biogenesis. New York: Springer-Verlag/Wien.

    Google Scholar 

  • JENSEN, E. V., GREENE, G. L., CLOSS, L. E., DESOMBRE, E. R. & NADJI, M. (1982) Receptors reconsidered: A20 year perspective. Recent Progress in Hormone Research 38, 1–40.

    PubMed  Google Scholar 

  • KUJAWA, K. A., TANZER, L. & JONES, K. J. (1995) Inhibition of the accelerative effects of testosterone on hamster facial nerve regeneration by the antiandrogen flutamide. Experimental Neurology 133, 138–143.

    PubMed  Google Scholar 

  • JONES, K. J., DURICA, T. E. & JACOB, S. K. (1997) Gonadal steroid preservation of central synaptic input to hamster facial motoneurons following peripheral axotomy. Journal of Neurocytology 26, 257–266.

    PubMed  Google Scholar 

  • JONES, K. J., HARRINGTON, C. A., CHIKARAISHI, D. M. & PFAFF, D. W. (1990) Steroid hormone regulation of ribosomal RNA in rat hypothalamus: Early detection using in situ hybridization and precursor-product ribosomal DNA probes. Journal of Neuroscience 10, 1513–1521.

    PubMed  Google Scholar 

  • JONES, K. J. & LAVELLE, A. (1986) Differential effects of axotomy on immature and mature hamster facial neurons: Atime course study of initial nucleolar and nuclear changes. Journal of Neurocytology 15, 197–206.

    PubMed  Google Scholar 

  • JONES, K. J. & OBLINGER, M. M. (1994) Androgenic regulation of tubulin gene expression in axotomized hamster facial motoneurons. Journal of Neuroscience 14, 3620–3627.

    PubMed  Google Scholar 

  • JONES, K. J., STORER, P. D., DRENGLER, S. M. & OBLINGER, M. M. (1999) Differential regulation of cytoskeletal gene expression in hamster facial motoneurons: Effects of axotomy and testosterone treatment. Journal of Neuroscience Research 57, 817–823.

    PubMed  Google Scholar 

  • KINDERMAN, N. B., HARRINGTON, C. A., DRENGLER, S. M. & JONES, K. J. (1998) Ribosomal RNA transcriptional activation and processing in hamster facial motoneurons: Effects of axotomy with or without exposure to testosterone. Journal of Comparative Neurology 401, 205–216.

    PubMed  Google Scholar 

  • KINDERMAN, N. B. & JONES, K. J. (1993) Testosterone enhancement of the nerve cell body response to injury: Evidence using in situ hybridization and ribosomal DNA probes. Journal of Neuroscience 13, 1523–1532.

    PubMed  Google Scholar 

  • KINDERMAN, N. B. & LAVELLE, A. (1976) Ultrastructural changes in the developing nucleolus following axotomy. Brain Research 108, 237–247.

    PubMed  Google Scholar 

  • KUJAWA, K. A., JACOB, J. M. & JONES, K. J. (1993) Testosterone regulation of the regenerative properties of injured rat sciatic motor neurons. Journal of Neuroscience Research 35, 268–273.

    PubMed  Google Scholar 

  • KUJAWA, K. A. & JONES, K. J. (1990) Testosterone-induced acceleration of recovery from facial paralysis in male hamsters: Temporal requirements of hormone exposure. Physiology and Behavior 48, 765–768.

    PubMed  Google Scholar 

  • KUJAWA, K. A. & JONES, K. J. (1995) Trophic actions of gonadal steroids on neuronal functioning normally and following injury. Advances in Neural Science 2, 131–152.

    Google Scholar 

  • KUJAWA, K. A., KINDERMAN, N. B. & JONES, K. J. (1989) Testosterone-induced acceleration of recovery from facial paralysis following crush axotomy of the facial nerve in male hamsters. Experimental Neurology 105, 80–85.

    PubMed  Google Scholar 

  • KURZ, E. M., SENGELAUB, D. R. & ARNOLD, A. P. (1986) Androgens regulate dendritic length of sexually dimorphic mammalian motoneurons in adulthood. Science 232, 395–398.

    PubMed  Google Scholar 

  • LAVELLE, A. & LAVELLE, F. (Eds.) (1984) Neuronal Reaction to Injury During Development. New York: Academic Press.

    Google Scholar 

  • LEEDY, M. G., BEATTIE, M. S. & BRESNAHAN, J. C. (1987) Testosterone-induced plasticity of synaptic inputs to adult mammalian motoneurons. Brain Research 424, 386–390.

    PubMed  Google Scholar 

  • LIEBERMAN, A. R. (1971) The axon reaction:Areview of the principal features of perikaryal responses to axon injury. International Review of Neurobiology 14, 49–124.

    PubMed  Google Scholar 

  • LUBISCHER, J. L. & ARNOLD, A. P. (1995) Axotomy transiently down-regulates androgen receptors in motoneurons of the spinal nucleus of the bulbocavernosus. Brain Research 694, 61–68.

    PubMed  Google Scholar 

  • LUBISCHER, J. L., JORDAN, C. L. & ARNOLD, A. P. (1992) Transient and permanent effects of androgen during synapse elimination in the levator ani muscle of the rat. Journal of Neurobiology 23, 1–9.

    PubMed  Google Scholar 

  • MATSUMOTO, A. (1992) Hormonally induced synaptic plasticity in the adult neuroendocrine brain. Zoological Science 9, 679–695.

    Google Scholar 

  • MATSUMOTO, A., ARAI, Y. & HYODO, S. (1993) Androgenic regulation of expression of beta-tubulin messenger ribonucleic acid in motoneurons of the spinal nucleus of the bulbocavernosus. Journal of Neuroendocrinology 5, 357–363.

    PubMed  Google Scholar 

  • MATSUMOTO, A., MICEVYCH, P. E. & ARNOLD, A. P. (1988) Androgen regulates synaptic input to motoneurons of the adult spinal cord. Journal of Neuroscience 8, 4168–4176.

    Google Scholar 

  • MCEWEN, B. S. & ALVES, S. E. (1999) Estrogen actions in the central nervous system. Endocrine Reviews 20, 279–307.

    PubMed  Google Scholar 

  • MCQUARRIE, I. G. (1978) The effect of a conditioning lesion on the regeneration of motor axons. Brain Research 152, 597–602.

    PubMed  Google Scholar 

  • MCQUARRIE, I. G. (1981) Acceleration of Axonal Regeneration in Rat Somatic Motoneurons by Using a Conditioning Lesion. New York: Raven Press.

    Google Scholar 

  • MCQUARRIE, I. G. (1983) Role of the axonal cytoskeleton in the regenerating nervous system. In Nerve, Organ and Tissue Regeneration: Research Perspectives (edited by SEIL, F. J.) pp. 51–88. New York: Academic Press.

    Google Scholar 

  • NEW, G. A., HENDRICKSON, B. R. & JONES, K. J. (1989) Induction of heat shock protein 70 mRNA in adult hamster facial nuclear groups following axotomy of the facial nerve. Metabolic Brain Research 4, 273–279.

    Google Scholar 

  • NEWFRY, G. A. & JONES, K. J. (1998) Differential effects of facial nerve transection on hsp70 protein expression in the developing and adult hamster facial nucleus. Metabolic Brain Disease 13, 253–257.

    PubMed  Google Scholar 

  • NORTON, W., AQUINO, D., HOZUMI, I., CHIU, F. & BRONSON, C. (1992) Quantitative aspects of reactive gliosis: A review. Neurochemical Research 17, 877–885.

    PubMed  Google Scholar 

  • NOVER, L. (1984) Heat Shock Response of Eukaryotic Cells. Berlin: Springer-Verlag.

    Google Scholar 

  • OBLINGER, M. M. & LASEK, R. J. (1984) A conditioning lesion of the peripheral axons of dorsal root ganglion cells accelerates regeneration of only their peripheral axons. Journal of Neuroscience 4, 1736–1744.

    Google Scholar 

  • OBLINGER, M. M. & WONG, J. (1990) Changes in cytoskeletal gene expression during axonal regrowth in mammalian neurons. In Advances in Neural Regeneration Research (edited by SEIL, F. J.) pp. 1–19.

  • PINTER, M. J. & VANDEN NOVEN, S. (1989) Effects of preventing reinnervation of axotomized spinal motoneurons in the cat. I. Motoneuron electrical properties. Journal of Neurophysiology, 62, 311–324.

    PubMed  Google Scholar 

  • POYET, P. & LABRIE, F. (1985) Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megesterol acetate. Molecular and Cellular Endocrinology 42, 283–288.

    PubMed  Google Scholar 

  • PRATT, W. B. & TOFT, D. O. (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocrine Reviews 18, 306–360.

    PubMed  Google Scholar 

  • SUMNER, B. E. H. & SUTHERLAND, F. I. (1973) Quantitative electron microscopy on the injured hypoglossal nucleus in the rat. Journal of Neurocytology 2, 315–328.

    PubMed  Google Scholar 

  • SVENSSON, M. & ALDSKOGIUS, H. (1993) Synaptic density of axotomized hypoglossal motoneurons following pharmacological blockade of the microglial cell proliferation. Experimental Neurology 120, 123–131.

    PubMed  Google Scholar 

  • TANZER, L. & JONES, K. J. (1997) Gonadal steroid regulation of hamster facial nerve regeneration: Effects of dihydrotestosterone and estradiol. Experimental Neurology 146, 258–264.

    PubMed  Google Scholar 

  • TISSIERES, A., MITCHELL, H. K. & TRACY, U. M. (1974) Protein synthesis in salivary glands of D. melanogaster: Relation to chromosome puffs. Journal of Molecular Biology 84, 389–398.

    PubMed  Google Scholar 

  • TORRES-ALEMAN, I., REJAS, T. M., PONS, S. & GARCIA-SEGURA, L. M. (1992) Estradiol promotes cell shape changes and glial fibrillary acidic protein redistribution in hypothalamic-astrocytes in vitro: A neuronmediated effect. Glia 6, 180–187.

    PubMed  Google Scholar 

  • TOWNSLEY, J. D. & BRODIE, H. J. (1968) Studies on the mechanism of estrogen biosynthesis. III. The stereochemistry of aromatization of C19 and C18 steroids. Biochemistry 7, 33–40.

    PubMed  Google Scholar 

  • VELDSCHOLTE, J., BERREVOETS, C. A., ZEGERS, N. D., VAN DER KWAST, T. H., GROOTEGOED, J. A. & MULDER, E. (1992) Hormone-induced dissociation of the androgen receptor-heat-shock protein complex: Use of a new monoclonal antibody to distinguish transformed from nontransformed receptors. Biochemistry 31, 7422–7430.

    PubMed  Google Scholar 

  • VITA, G., DATTOLA, R., GIRLANDA, P., OTERI, G., PRESTI, F. L. & MESSINA, C. (1983) Effects of steroid hormones on muscle reinnervation after nerve crush in rabbit. Experimental Neurology 80, 279–287.

    PubMed  Google Scholar 

  • WATSON, W. E. (1968) Observations on the nucleolar and total cell body nucleic acid of injured nerve cells. Journal of Physiology 196, 655–676.

    PubMed  Google Scholar 

  • WHELLY, S. M. (1985) Regulation of uterine nucleolar RNA synthesis by estrogens. Biology of Reproduction 33, 1–10.

    PubMed  Google Scholar 

  • XU, L., LEE, J. E. & GIFFARD, R. G. (1999) Overexpression of bcl-2, bcl-XL or hsp70 in murine cortical astrocytes reduces injury of co-cultured neurons. Neuroscience Letters 277, 193–197.

    PubMed  Google Scholar 

  • YEAGLE, S. P., MAYER, R. F. & MAX, S. R. (1983) Contractile properties of rat fast-twitch skeletal muscle during reinnervation: Effects of testosterone and castration. Experimental Neurology 82, 344–357.

    PubMed  Google Scholar 

  • YU, W.-H. A. (1982a) Sex difference in the regeneration of the hypoglossal nerve in rats. Brain Research 238, 404–406.

    PubMed  Google Scholar 

  • YU, W.-H. A. (1982b) Effects of testosterone on the regeneration of the hypoglossal nerve in rats. Experimental Neurology 77, 129–141.

    PubMed  Google Scholar 

  • YU, W.-H. A. & MC GINNIS, M. Y. (1986) Androgen receptor levels in cranial nerve nuclei and tongue muscles in rats. Journal of Neuroscience 6, 1302–1307.

    PubMed  Google Scholar 

  • YU, W.-H. A. & SRINIVASAN, R. (1981) Effect of testosterone and 5?-dihydrotestosterone on regeneration of the hypoglossal nerve in rats. Experimental Neurology 71, 431–435.

    PubMed  Google Scholar 

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Jones, K.J., Alexander, T.D., Brown, T.J. et al. Gonadal steroid enhancement of facial nerve regeneration: Role of heat shock protein 70. J Neurocytol 29, 341–349 (2000). https://doi.org/10.1023/A:1007157105835

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