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Impressum
GDNF induces wound healing and cell migration through RET and the MAP-kinase pathway.
Kruse F. E., You L., Ebner S.
Department of Ophthalmology, University of Heidelberg, INF 400, 69120 Heidelberg
Purpose: Nerve growth factor (NGF) has found application in treatment
of non healing corneal ulcers in humans. The present study investigates
the effect of GDNF, another neuroptophic factor with similar functions
in the nervous system on cell migration and wound healing of corneal epithelial
cells. Furthermore an analysis of signal transduction pathways induced
by GDNF was performed
Methods: Migration was quantified in a modified Boyden chamber.
In-vitro wound healing was evaluated by time-lapse video-images from scratch
wounds. MAP kinase and FAK signaling was investigated by western blotting
with phospho-specific antibodies against the phosphorylated forms of GDNF
receptor Ret Raf, MEK 1/2, Elk 1, Erk and p90Rsk. Phosphorylation of paxillin
and FAK was also studied. Herbimycin and ret inhibitors were used
Results: GDNF (250ng/ml) significantly enhanced migration (p>0.01)
and in vitro wound closure (p>0.0001) which can be blocked by herbimycin.
GDNF caused time- and dose dependent phosphorylation of its receptor ret
as well as various components of the MAP-kinase pathway (cRaf, MEK 1,
Erk 1/2 and Elk but not p90Rsk). Herbimycin blocked the effect of GDNF
on MAP-kinase signal transduction. In addition FAK was phosphorylated
which in turn led to phosphorylation of paxillin.
Conclusions: Our results show that the MAK-kinase and FAK signal
transduction in the human cornea is initiated by the GDNF-GDNFR-a/ret
signaling system. The enhancement of cellular migration seems to be mediated
through FAK phopshorylation and is one of the primary biological effects
of GDNF in the cornea. GDNF signals through the MAP-kinase pathway and
its function is similar to that of other neurotrophins. Our data support
the idea that neurotrophins can be used to treat corneal disorders that
are based on impaired migration of the corneal epithelium. (Kr 993/12-1)