Retinal Degeneration in SHP–1 Protein–Tyrosine Phosphatase–Deficient "Viable Motheaten" Mice

Abstract

Abstract: : Purpose: Viable motheaten mice (abbreviated gene symbol me^v) 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, me^v/me^v 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 me^v/me^v 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 me^v/me^v mice is determined at the level of bone marrow progenitor cells, bone marrow from me^v/me^v mice was transferred into irradiated syngeneic +/+ hosts. B–cell deficient me^v/me^v Igh–6^null mice were generated to assess the role of autoantibodies in the development of RD. Results: Fundus examinations of me^v/me^v mice demonstrated numerous, small, white foci, giving a mottled appearance of the entire retina. The retinal vasculature was normal in 16 week–old me^v/me^v mice, the upper limit for lifespan in these mutant mice. Both scotopic and photopic ERGs were abnormal in me^v/me^v mice. The a– and b–wave amplitudes are diminished to a similar degree beginning at 4 weeks of age. Histologic examination of me^v/me^v mice demonstrated photoreceptor loss beginning at age 4 weeks. TEM of me^v/me^v 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 me^v/me^v and control mice. Autoantibodies do not contribute to RD as B–cell deficient me^v/me^v Igh–6^null mice had no attenuation of photoreceptor cell loss as compared to age matched me^v/me^v mice. Histopathologic examination of lungs and retinas from recipients of me^v/me^v marrow, four weeks post transplantation, revealed the classic acidophilic macrophage pneumonia of me^v/me^v mice but no retinal degeneration. Conclusions: me^v/me^v 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.

Keywords: retinal degenerations: cell biology • retinal pigment epithelium • signal transduction