Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor
Section snippets
Intraorbital optic nerve transection and retrograde labeling
Adult, female Sprague–Dawley rats (225–250 g; Charles River), which were housed in a Level B pathogen-free environment, were used in all experiments. All efforts were made to minimize animal suffering and to use only the number of animals necessary to produce reliable scientific data. Experimental procedures were carried out according to the guidelines of the Canadian Council on Animal Care. Rats were anesthetized with i.p. injections of 7% chloral hydrate (0.42 mg/g of body weight) during
Localization of GDNF in the mammalian retina
GDNF mRNA has previously been localized in the retina (Nosrat et al., 1996). In order to determine which retinal cells express GDNF, GDNF immunohistochemistry was carried out on transverse retinal sections. GDNF was localized to cells in the ganglion cell layer, photoreceptor outer segments, and the retinal pigment epithelium (Fig. 1A). Intense GDNF immunoreactivity was also observed in RGC axon fascicles (Fig. 1B). In order to determine if the GDNF immunoreactive cells in the ganglion cell
Discussion
In the present study we localized GDNF and its high affinity receptor GFRα-1 in the mammalian retina. We also demonstrated that neurturin has neurotrophic effects on axotomized RGCs in vivo. Furthermore, combined administration of neurturin with GDNF produces enhanced RGC survival after axotomy. This enhanced effect was not as striking as the additive RGC survival observed when either neurturin or GDNF was combined with BDNF. These findings suggest that neurturin, GDNF, and BDNF may act through
Conclusion
The results of the present study suggest that RGCs and Müller cells express GFRα-1, the high affinity receptor for GDNF. RGCs may be directly responsive to GDNF, since previous findings suggest that RGCs express Ret. We have also shown for the first time that neurturin protects injured RGCs following optic nerve transection. Combined administration of neurturin with GDNF or BDNF is more effective in enhancing the survival of axotomized RGCs than intraocular administration of each factor
Acknowledgements
This work was supported by Natural Sciences and Engineering Research Council of Canada Operating Grant OGP0171190 to A.K.B. and an NSERC studentship to P.D.K. P.D.K. is supported by the Ontario Neurotrauma Foundation.
References (80)
- et al.
Neuroprotective utility and neurotrophic action of neurturin in postnatal motor neurons: comparison with GDNF and persephin
Mol. Cell. Neurosci.
(1999) - et al.
Rod outer segment maintenance is enhanced in the presence of bFGF, CNTF and GDNF
Exp. Eye Res.
(1998) - et al.
Prevention of dopaminergic neuron death by adeno-associated virus vector-mediated GDNF gene transfer in rat mesencephalic cells in vitro
Neurosci. Lett.
(1998) - et al.
Differential signaling of glial cell line-derived neurothrophic factor and brain-derived neurotrophic factor in cultured ventral mesencephalic neurons
Neuroscience
(1999) - et al.
Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase
J. Biol. Chem.
(1999) - et al.
TGFbeta trophic factors differentially modulate motor axon outgrowth and protection from excitotoxicity
Exp. Neurol.
(2000) - et al.
GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF
Cell
(1996) - et al.
GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family
J. Biol. Chem.
(1997) - et al.
Effects of GDNF on retinal ganglion cell survival following axotomy
Vis. Res.
(1998) - et al.
Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo
Neuron
(1993)