Regulation and effects of GDF-15 in the retina following optic nerve crush
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Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-β superfamily and is ubiquitously expressed in the central nervous system. It is prominently upregulated in cerebral cortical and ischemic lesion paradigms. GDF-15 robustly promotes the survival of lesioned nigrostriatal dopaminergic neurons in vivo; GDF-15-deficient mice exhibit progressive postnatal motor and sensory neuron losses implying essential functions of GDF-15 in neuronal survival. We show that GDF-15 mRNA and protein are, respectively, six-fold and three-fold upregulated in the murine retina at 1 day after optic nerve crush, slightly elevated mRNA levels being maintained until day 28. However, the magnitude and time course of retinal ganglion cell (RGC) death are indistinguishable in knockout and control mice. Selected mRNAs implicated in the regulation of the death vs. survival of RGCs, including ATF3, Bad, Bcl-2 and caspase-8, were similarly regulated in both knockout and control retinae. Immunohistochemistry for tyrosine hydroxylase and choline acetyltransferase revealed no differences in staining patterns in the two genotypes. mRNA and protein levels of galanin, a putative neuroprotective factor and positive regulator of neuron survival and axonal regeneration, were prominently upregulated after crush in knockout retinae at day 3, as compared with control retinae, suggesting that GDF-15 acts as a physiological regulator of galanin. GDF-15 is therefore prominently upregulated in the retina after optic nerve crush but does not directly interfere with the magnitude and temporal progression of RGC death.
KeywordsGDF-15 Retina Optic nerve crush Retinal ganglion cell Mouse
We thank Ioannis Patrozos, Attila Magyar and Katrin Huber-Wittmer for support and constructive discussion.
- Hökfelt T, Aman K, Arvidsson U, Bedecs K, Ceccatelli S, Hulting AL, Langel U, Meister B, Pieribone V, Bartfai T (1992) Galanin message-associated peptide (GMAP)- and galanin-like immunoreactivities: overlapping and differential distributions in the rat. Neurosci Lett 142:139–142PubMedCrossRefGoogle Scholar
- Nadal-Nicolás FM, Jiménez-López M, Sobrado-Calvo P, Nieto-López L, Cánovas-Martínez I, Salinas-Navarro M, Vidal-Sanz M, Agudo M (2009) Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas. Invest Ophthalmol Vis Sci 50:3860–3868PubMedCrossRefGoogle Scholar
- Parrilla-Reverter G, Agudo M, Sobrado-Calvo P, Salinas-Navarro M, Villegas-Pérez MP, Vidal-Sanz M (2009) Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury: a quantitative in vivo study. Exp Eye Res 89:32–41PubMedCrossRefGoogle Scholar
- Schober A, Böttner M, Strelau J, Kinscherf R, Bonaterra GA, Barth M, Schilling L, Fairlie WD, Breit SN, Unsicker K (2001) Expression of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J Comp Neurol 439:32–45PubMedCrossRefGoogle Scholar
- Strelau J, Sullivan A, Böttner M, Lingor P, Falkenstein E, Suter-Crazzolara C, Galter D, Jaszai J, Krieglstein K, Unsicker K (2000) Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci 20:8597–8603PubMedGoogle Scholar
- Zhang S-J, Buchthal B, Lau D, Hayer S, Dick O, Schwaninger M, Veltkamp R, Zou M, Weiss U, Bading H (2011) A signalling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J Neurosci 31:4978–4990PubMedCrossRefGoogle Scholar