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E. Tamm, A. Ohlmann, M. Scholz, A. Goldwich, C. Flügel–Koch, B.K. Chauhan, A. Cvekl; In Vivo Evidence that Norrie Disease Protein (NDP) is a Growth Factor for Retinal Neurons and Capillaries . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5326.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the function of Norrie Disease Protein (NDP), a 133 aa secreted polypeptide with the predicted tertiary structure of a cystine knot growth factor (Meitinger et al., Nat. Genet. 1993). Mutations in NDP cause Norrie's disease characterized by degenerative changes in the retina that lead to blindness. NDP–deficient mice (Berger et al., HMG 1996) show a continuous loss of retinal ganglion cells starting at postnatal day (P) 7 and lack retinal capillaries (Richter et al., IOVS 1998). Methods: Four independent transgenic mouse lines were developed that overexpress NDP in the eye under control of the lens–specific ßB1–crystallin promoter. Transgenic integration and copy number was characterized by Southern blot analysis. The phenotype of transgenic mice was analyzed from P2 to P28. Results: Overexpression of NDP and its mRNA was confirmed by northern blot hybridization, and western blot analyses using antibodies that were generated against recombinant NDP. Three transgenic lines showed high expression of NDP mRNA, in comparison to one line with moderate expression. At P2, central and peripheral retinas from transgenic animals were considerably thicker than that of control littermates. The increase in central thickness was due to a 50% increase in retinal ganglion cells (RGC) and a 27% increase in nuclear layer neurons (NLN). In the peripheral retina, RGC increased by 73 % and NLN by 62%. The differences were statistically significant (p < 0.05) in high expressing lines. No significant changes were observed in the transgenic line with moderate expression, indicating that the dose of transgenic NDP is a critical factor for the retinal phenotype of ßB1–NDP mice. Transgenic animals had significantly more capillaries in the posterior hyaloid membrane, and overexpressed Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF). In vitro, proliferation of human capillary endothelial cells was induced in the presence of NDP–overexpressing lenses. When NDP–overexpressing mice were crossbred with NDP–deficient mice, the phenotype of NDP–deficient mice was completely rescued. In double ßB1–NDP/NDP–deficient mice, a loss of retinal ganglion cells was not observed and the retinal vascularization was normal. Conclusions: NDP has a growth stimulatory activity for retinal neurons and capillaries, and is critically required to maintain the normal structure of the retina.
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