The object of this pilot study is to determine how constitutive loss of the adhesion receptor v5 integrin affects the retinal. In the eye, the primary 5 integrin expression is the retinal pigment epithelium (RPE). v5 receptors are the only integrin family adhesion protein that localize to the apical surface of human and rodent RPE facing interphotoreceptor matrix and photoreceptor outer segments. In murine retina. v5 onset of expression in RPE precisely coincides with the formation of mature interactions between the RPE apical surface and photoreceptor outer segments. Such interactions, each of which is critical for long-term photoreceptor viability, include specific adhesive contacts that maintain tight attachment of the neural retinal to RPE and the daily phagocytosis of shed outer segment fragments (OS) by RPE. Isolated RPE cells utilize v5 receptors to attach to vitronectin substrate suggesting that v5 may mediate RPE-neural retina adhesion either directly, by interacting with photoreceptor outer segments or, indirectly, by binding to IPM components that also attach to outer segments. Moreover, RPE in culture requires v5 integrin for OS binding that initiates OS internalization. Thus, much in vitro evidence suggests an important role of v5 in RPE. The proposed experiments will evaluate the contribution of v5 receptors to retinal health and function in vivo. To this end, they will survey retina characteristics of age-matched wild-type and 5 knock-out mice from youth to old age. This strategy will identify retina changes caused by loss of v5 receptors and, furthermore, distinguished between direct (early onset) effects. Specifically, this study will (1) characterize the effects of 5 integrin knock-out on retinal function and morphology using electroretinogram recordings, light and electron microscopy; (02) test whether v5 integrin contributes to RPE, adhesion to neural retina using mechanical assays to quantify the adhesive force of RPE and neural retina; and (3) test whether v5 integrin participates in phagocytosis of shed OS by RPE using microscopy and functional assays to compare the OS uptake kinetics and the phagocytic capacity of wild-type and 5 null RPE. Abnormal RPE-neural retina interactions cause retinal degeneration in humans and rodents. The mechanisms of these interactions and the unique localization of v5 integrin in RPE are conserved among species. Exploring the 5 null mouse is thus important to understand human disease.
| Nandrot, Emeline F; Dufour, Eric M (2010) Mertk in daily retinal phagocytosis: a history in the making. Adv Exp Med Biol 664:133-40 |
| Nandrot, Emeline F; Finnemann, Silvia C (2006) Altered rhythm of photoreceptor outer segment phagocytosis in beta5 integrin knockout mice. Adv Exp Med Biol 572:119-23 |
| Finnemann, Silvia C; Nandrot, Emeline F (2006) MerTK activation during RPE phagocytosis in vivo requires alphaVbeta5 integrin. Adv Exp Med Biol 572:499-503 |
| Nandrot, Emeline F; Anand, Monika; Sircar, Mousumi et al. (2006) Novel role for alphavbeta5-integrin in retinal adhesion and its diurnal peak. Am J Physiol Cell Physiol 290:C1256-62 |
| Nandrot, Emeline F; Kim, Yoonhee; Brodie, Scott E et al. (2004) Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking alphavbeta5 integrin. J Exp Med 200:1539-45 |
| Finnemann, Silvia C (2003) Role of alphavbeta5 integrin in regulating phagocytosis by the retinal pigment epithelium. Adv Exp Med Biol 533:337-42 |
