Deficiency of SHP-1 Protein-Tyrosine Phosphatase in "Viable Motheaten" Mice Results in Retinal Degeneration

Viable motheaten mutant mice (abbreviated allele symbol me(v)) are deficient in Src-homology 2-domain phosphatase (SHP)-1, a critical negative regulator of signal transduction in hematopoietic cells. These mice exhibit immune dysfunction, hyperproliferation of myeloid cells, and regenerative anemia. This study focused on the role of SHP-1 in retinal homeostasis. Ophthalmoscopy, histology, transmission electron microscopy (TEM), electroretinography (ERG), immunohistochemistry, Western blot, bone marrow transplantation, and genetic crosses were performed for phenotypic characterization and functional studies of retinal degeneration (RD) in me(v)/me(v) mice. Fundus examinations of me(v)/me(v) mice revealed numerous, small white spots. Histologic examination demonstrated photoreceptor loss beginning at 3 weeks of age, and TEM revealed disorganization and reduction in the number of outer segments, as well as the presence of phagocytic cells in the subretinal space. Rod- and cone-mediated ERGs were abnormal. SHP-1 protein was expressed in mouse and human retinal lysates and was localized to the outer nuclear layer of the retina in me(v)/me(v) and control mice. Autoantibodies are not necessary for RD, as B-cell-deficient me(v)/me(v) Igh-6(tm1Cgn) mice had no attenuation of photoreceptor cell loss compared with age-matched me(v)/me(v) mice. Histologic examination of lungs and retinas from normal recipients of me(v)/me(v) marrow revealed the classic acidophilic macrophage pneumonia of me(v)/me(v) mice, but no retinal degeneration. me(v)/me(v) mice exhibit normal retinal development with the onset of RD at 3 weeks of age and a rapidly progressive loss of photoreceptors. These findings support the hypothesis that SHP-1 plays a critical role in retinal homeostasis.