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B.L. Lyons, R.S. Smith, R.E. Hurd, N.L. Hawes, L.M. Burzenski, L.D. Shultz; Retinal Degeneration in SHP–1 Protein–Tyrosine Phosphatase–Deficient "Viable Motheaten" Mice . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3620.
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Purpose: Viable motheaten mice (abbreviated gene symbol mev) are deficient in SHP–1, a critical negative regulator of signal transduction in hematopoietic cells. These mice exhibit severe immune dysfunction, hyperproliferation of myeloid cells and regenerative anemia. Additionally, mev/mev mice develop retinal degeneration (RD). Methods: Indirect ophthalmoscopy, histology, transmission electron microscopy (TEM), and electroretinography (ERG) were carried out to delineate the temporal progression of RD in mev/mev mice. Fluorescence angiography was utilized to evaluate retinal vascular integrity, and immunohistochemistry was used to detect caspase–3 expression to assess the role of apoptosis. Analysis of neural retinal and retinal pigment epithelium (RPE) cell lysates for SHP–1 protein was accomplished using Western blotting technique. To establish if the retinal degeneration of mev/mev mice is determined at the level of bone marrow progenitor cells, bone marrow from mev/mev mice was transferred into irradiated syngeneic +/+ hosts. B–cell deficient mev/mev Igh–6null mice were generated to assess the role of autoantibodies in the development of RD. Results: Fundus examinations of mev/mev mice demonstrated numerous, small, white foci, giving a mottled appearance of the entire retina. The retinal vasculature was normal in 16 week–old mev/mev mice, the upper limit for lifespan in these mutant mice. Both scotopic and photopic ERGs were abnormal in mev/mev mice. The a– and b–wave amplitudes are diminished to a similar degree beginning at 4 weeks of age. Histologic examination of mev/mev mice demonstrated photoreceptor loss beginning at age 4 weeks. TEM of mev/mev retinas revealed disorganization and reduction in number of outer segments, as well as phagocytic cells in the subretinal space. SHP–1 protein was expressed in the RPE but not in the retina of mev/mev and control mice. Autoantibodies do not contribute to RD as B–cell deficient mev/mev Igh–6null mice had no attenuation of photoreceptor cell loss as compared to age matched mev/mev mice. Histopathologic examination of lungs and retinas from recipients of mev/mev marrow, four weeks post transplantation, revealed the classic acidophilic macrophage pneumonia of mev/mev mice but no retinal degeneration. Conclusions: mev/mev exhibit normal retinal development with the onset of RD at 4 weeks of age and a rapidly progressive loss of photoreceptors. These findings support the hypothesis that SHP–1 is a critical signaling molecule necessary for normal retinal homeostasis, which may modulate interactions between photoreceptors and RPE.
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