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  Regulation and function of neuronal GTP-Ras in facial motor nerve regeneration

Makwana, M., Serchov, T., Hristova, M., Bohatschek, M., Gschwendtner, A., Kalla, R., et al. (2009). Regulation and function of neuronal GTP-Ras in facial motor nerve regeneration. Journal of Neurochemistry, 108(6), 1453-1463.

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 Creators:
Makwana, M.1, Author
Serchov, T.1, Author
Hristova, M.1, Author
Bohatschek, M.2, Author           
Gschwendtner, A.2, Author           
Kalla, R.2, Author           
Liu, Z. Q.2, Author           
Heumann, R.1, Author
Raivich, G.2, Author           
Affiliations:
1[Makwana, Milan; Hristova, Mariya; Bohatschek, Marion; Raivich, Genndij] UCL, EGA Inst Womens Hlth, Dept Obstet & Gynaecol, Perinatal Brain Repair Grp, London WC1E 6HX, England.; [Serchov, Tsvetan; Heumann, Rolf] Ruhr Univ Bochum, Fak Chem, Dept Mol Neurobiochem NC7, D-4630 Bochum, Germany.; [Raivich, Genndij] UCL, Dept Anat & Dev Biol, London, England., ou_persistent22              
2Emeritus Group: Neuromorphology / Kreutzberg, MPI of Neurobiology, Max Planck Society, ou_1113551              

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Free keywords: axonal regeneration; central sprouting; lymphocyte influx; motor neuron cell death; oncogene
 Abstract: Activation of Ras into the GTP-binding, 'ON' state is a key switch in the neurotrophin-mediated neuronal survival and neurite outgrowth, in vitro as well as in vivo. In the current study we explored changes in GTP-Ras levels following facial nerve injury and the ensuing regeneration and the effects of perturbing these changes in vivo using synapsin-promoter mediated neuronal expression of constitutively active Val12H-Ras (synRas). Quantification of GTP-Ras and total Ras revealed a precipitous drop in the relative GTP-Ras levels in the axotomized facial motor nucleus, to 40% of normal levels at 2 days after cut, followed by a partial recovery to 50-65% at 4-28 days. On western blots, control and axotomized nuclei from synRas mutants showed a 2.2- and 2.5-fold elevation in GTP-Ras, respectively, compared with their wild type littermate controls (p < 5%, anova, TUKEY post-hoc), with the levels in the axotomized synRas nucleus slightly but not significantly above that in the uninjured littermate control (p = 9.9%). Similar increase was also observed in the pERK but not pAKT targets of the Ras cascade. This moderate elevation of GTP-Ras strongly curtailed post-traumatic neuronal cell death (-65%), the influx of T-cells (-48%) as well as other parameters of neuroinflammatory response. Although synRas did not affect the speed of axonal regeneration or functional recovery it caused a very pronounced increase in central axonal sprouting. These current data emphasize the role of reduced active Ras, and by extension, the reduced overall level of retrograde neurotrophin signalling after axotomy, in mediating post-traumatic cell death and inflammation and in restricting the sprouting response. Moreover, the neuroprotective and central sprouting-enhancing effects of neuronal Val12H-Ras could help promote recovery in CNS injury.

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Language(s): eng - English
 Dates: 2009-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 429922
ISI: 000263696300012
 Degree: -

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Title: Journal of Neurochemistry
  Alternative Title : J. Neurochem.
Source Genre: Journal
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Pages: - Volume / Issue: 108 (6) Sequence Number: - Start / End Page: 1453 - 1463 Identifier: ISSN: 0022-3042