Elsevier

Neuroscience

Volume 74, Issue 2, 19 July 1996, Pages 553-565
Neuroscience

Change in the molecular phenotype of Schwann cells upon transplantation into the central nervous system: down-regulation of c-jun

https://doi.org/10.1016/0306-4522(96)00199-6Get rights and content

Abstract

Activated Schwann cells such as those in the distal stump of a cut peripheral nerve, or those cultured in vitro, develop a molecular phenotype very different from that of quiescent Schwann cells, and express high levels of the transcription factor c-jun. We studied the expression of c-jun messenger RNA, by in situ hybridization, and Jun-like immunoreactivity of Schwann cells in segments of peripheral nerve, or in cell suspensions grafted into the adult rat brain. Schwann cells rapidly lost their Jun immunopositivity, and down-regulated expression of c-jun messenger RNA once implanted into the brain, and only the Schwann cells contained in the portion of peripheral nerve which remained outside the brain maintained Jun-like immunopositivity. c-jun messenger RNA was also down-regulated in the grafts, but more slowly than the protein; however, a proximodistal gradient in the level of expression of c-jun messenger RNA along the graft, comparable to that found for Jun immunoreactivity, was not detected. Schwann cells transplanted into the lesioned central nervous system promote regeneration of some injured central nervous system axons, but this regenerative response is always much more limited than peripheral nervous system regeneration.

We suggest a correlation between the limited regeneration of central nervous system axons into peripheral nerve grafts and the loss of c-jun expression in Schwann cells following exposure to the central nervous system environment.

Section snippets

Animals

All experimental procedures were carried out on adult male and female Sprague–Dawley rats (body weight 180–300 g; bred at University College London and the MRC Laboratory of Molecular Biology) deeply anaesthetized with 2% halothane (Fluothane, ICI, U.K.) or with equithesin (4 ml/kg). Sprague–Dawley rat pups aged postnatal day 1 (P1)–P4 were killed by decapitation.

Schwann cells culture

Sciatic nerves were obtained from P1–P4 Sprague–Dawley rat pups, collected in L15 medium (GIBCO, U.K.) treated for 1 h with 0.1%

Fresh peripheral nerve segments crafted into thalamus or cerebellum

We examined by light microscopy 16 grafts, between 6 and 30 dpo; nine grafts had been implanted into the cerebellum, and seven into the thalamus (Table 1).In sections of brain immunostained for Jun, immunopositive neuronal nuclei were present in several brain regions such as the entorhinal cortex, hippocampus and thalamus, in agreement with other studies.[29]In addition, some neurons in the thalamic reticular nucleus and deep cerebellar nuclei were Jun immunoreactive (these data will be

Discussion

The key finding in the present study is that Schwann cells exposed to the CNS environment, whether as components of a freshly transected or predegenerate PN graft, or as a cell suspension of cultured cells, undergo a down-regulation of c-jun expression, as shown both by in situ hybridization and immunohistochemistry. This finding contrasts strongly with observations in the activated Schwann cells of the distal stump of an injured PN in vivo or in isolated Schwann cells in culture; in both of

Conclusions

In conclusion, exposure of Schwann cells to the CNS environment causes a rapid down-regulation of their c-jun levels. In vitro c-jun expression in Schwann cell seems to correlate with their ability to proliferate,[58]as well as their ability to promote neurite outgrowth,[43]thus switching off c-jun in transplanted Schwann cells may be responsible for a reduced ability of Schwann cells to interact with injured CNS axons, and to promote their growth and maturation. The levels of expression of c-

Acknowledgements

We thank Professor A. R. Lieberman for helpful discussion and continued support. We also thank M. Turmaine and S. Miah for help with the electron microscopy and the Wellcome Trust (Grant no. 036926/1.5) for financial support.

References (61)

  • A Lin et al.

    Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity

    Cell

    (1992)
  • T.E Morgan et al.

    TGF-β1 mRNA increases in macrophages/microglial cells of the hippocampus in response to deafferentation and kainic acid induced neurodegeneration

    Expl Neurol.

    (1993)
  • D.R Morrow et al.

    Differential regenerative growth of CNS axons into tibial and peroneal nerve grafts in the thalamus of adult rats

    Expl Neurol.

    (1993)
  • R.G Pellegrino et al.

    Schwann cell mitosis in response to regenerating peripheral axons in vivo

    Brain Res.

    (1985)
  • C.M Pfarr et al.

    Mouse jun D negatively regulates fibroblast growth and antagonizes transformation by ras

    Cell

    (1994)
  • G.A Robinson

    Immediate early gene expression in axotomized and regenerating retinal ganglion cells of the adult rat

    Molec. Brain Res.

    (1994)
  • R Schule et al.

    Functional antagonism between oncoprotein c-jun and the glucocorticoid receptor

    Cell

    (1990)
  • Aguayo A. J. (1985) Axonal regeneration from injured neurons in the adult mammalian central nervous system. In Synaptic...
  • P Angel et al.

    Oncogene jun encodes a sequence-specific transactivator similar to AP-1

    Nature

    (1988)
  • J Arias et al.

    Activation of cAMP and mitogen responsive genes relies on a common nuclear factor

    Nature

    (1994)
  • J Auwerx et al.

    AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth

    Oncogene

    (1992)
  • M Bähr et al.

    Functional status influences the ability of Schwann cells to support adult rat retinal ganglion cell survival and axonal regrowth

    Expl Neurol.

    (1989)
  • K.S Bedi et al.

    Adult rat dorsal root ganglion neurons extend neurites on predegenerated but not on normal peripheral nerves in vitro

    Eur. J. Neurosci.

    (1992)
  • D Benbrooks et al.

    Heterodimer formation between CREB and JUN proteins

    Oncogene

    (1990)
  • W Beuche et al.

    The role of non-resident cells in wallerian degeneration

    J. Neurocytol.

    (1984)
  • D Bohmann et al.

    Human proto-oncogene c-jun encodes a DNA-binding protein with structural and functional properties of transcription factor AP1

    Science

    (1987)
  • T.J Bos et al.

    Efficient transformation of chicken embryo fibroblasts by c-jun requires structural modifications in coding and non-coding sequences

    Gene Dev.

    (1990)
  • M.C Brown et al.

    Poor growth of mammalian motor and sensory axons into intact proximal nerve stumps

    Eur. J. Neurosci.

    (1991)
  • G Campbell et al.

    Regeneration of adult rat CNS axons into peripheral nerve autografts: ultrastructural studies of the early stages of axonal sprouting and regenerative axonal growth

    J. Neurocytol.

    (1992)
  • M Castellazzi et al.

    Overexpression of c-jun, jun B, or jun D affects cell growth differently

    Proc. natn. Acad. Sci. U.S.A.

    (1991)
  • Cited by (11)

    View all citing articles on Scopus
    View full text