Summary: Aging contributes to the appearance of several retinopathies and is the largest risk factor for aged‐related macular degeneration, major cause of blindness in the elderly population. Accumulation of undegraded material as lipofuscin represents a hallmark in many pathologies of the aged eye. Autophagy is a highly conserved intracellular degradative pathway that plays a critical role in the removal of damaged cell components to maintain the cellular homeostasis. A decrease in autophagic activity with age observed in many tissues has been proposed to contribute to the aggravation of age‐related diseases. However, the participation of different autophagic pathways to the retina physiopathology remains unknown. Here, we describe a marked reduction in macroautophagic activity in the retina with age, which coincides with an increase in chaperone‐mediated autophagy (CMA). This increase in CMA is also observed during retinal neurodegeneration in the Atg5^flox/flox; nestin‐Cre mice, a mouse model with downregulation of macroautophagy in neuronal precursors. In contrast to other cell types, this autophagic cross talk in retinal cells is not bi‐directional and CMA inhibition renders cone photoreceptor very sensitive to stress. Temporal and cell‐type‐specific differences in the balance between autophagic pathways may be responsible for the specific pattern of visual loss that occurs with aging. Our results show for the first time a cross talk of different lysosomal proteolytic systems in the retina during normal aging and may help the development of new therapeutic intervention for age‐dependent retinal diseases.

Programmed cell death is an established developmental process in the nervous system. Whereas the regulation and the developmental role of neuronal cell death have been widely demonstrated, the relevance of cell death during early neurogenesis, the cells affected and the identity of regulatory local growth factors remain poorly characterized. We have previously described specific in vivo patterns of apoptosis during early retinal neurogenesis, and that exogenous insulin acts as survival factor (Díaz, B., Pimentel, B., De Pablo, F. and de la Rosa, E. J. (1999) Eur. J. Neurosci. 11, 1624-1632). Proinsulin mRNA was found to be expressed broadly in the early embryonic chick retina, and decreased later between days 6 and 8 of embryonic development, when there was increased expression of insulin-like growth factor I mRNA, absent or very scarce at earlier stages. Consequently, we studied whether proinsulin and/or insulin ((pro)insulin) action in prevention of cell death has physiological relevance during early neural development. In ovo treatment at day 2 of embryonic development with specific antibodies against (pro)insulin or the insulin receptor induced apoptosis in the neuroretina. The distribution of apoptotic cells two days after the blockade was similar to naturally occurring cell death, as visualized by TdT-mediated dUTP nick end labeling. The apoptosis induced by the insulin receptor blockade preferentially affected to the Islet1/2 positive cells, that is, the differentiated retinal ganglion cells. In parallel, the insulin survival effect on cultured retinas correlated with the activation of Akt to a greater extent than with the activation of MAP kinase. These results suggest that the physiological cell death occurring in early stages of retinal development is regulated by locally produced (pro)insulin through the activation of the Akt survival pathway.

Programmed cell death is a well established key process required for proper development of the nervous system. The regulatory and executor mechanisms controlling survival/death of projection neurons, as well as of other types of differentiated neurons and glial cells, have been studied intensely during neural development. Much less attention has been paid to earlier cell death events affecting neuroepithelial cells and recently born neurons and glial cells. We review here the reports on cell death during vertebrate retina development, our model system for many years, which has provided clear evidence of the importance of early neural cell death. We tentatively categorize the available observations in three death phases, namely morphogenetic cell death, early neural cell death and neurotrophic cell death. The magnitude and the precise regulation of the early phases of cell death are fully comparable to the much better characterized neurotrophic cell death. Therefore, early neural cell death deserves a profound dedicated study; this will help to obtain an integrated understanding of the development of the retina and other parts of the vertebrate nervous system.

Purpose. Retinitis pigmentosa (RP) is a heterogeneous group of inherited conditions that lead to blindness and for which there is no effective therapy. Apoptosis of photoreceptors is a common feature in animal models of the disease. Thus, the authors studied the therapeutic potential of proinsulin, an antiapoptotic molecule active during retinal development. methods. Transgenic mice expressing human proinsulin (hPi) in the skeletal muscle were generated in a mixed C57BL/6:SJL background and were back-crossed to a C57BL/6 background. Two independent lineages of transgenic mice were established in which hPi production in muscle was constitutive and not regulated by glucose levels. hPi levels in serum, muscle, and retina were determined with a commercial ELISA kit, visual function was evaluated by electroretinographic (ERG) recording, and programmed cell death was assessed by TUNEL. Immunohistochemistry was used to evaluate retinal structure preservation and oxidative damage. results. Transgenic expression of hPi in the rd10 retinal degeneration mouse model led to prolonged vision, as determined by ERG recording, in a manner that was related to the level of transgene expression. This attenuation of visual deterioration was correlated with a delay in photoreceptor apoptosis and with the preservation of retinal cytoarchitecture, particularly that of the cones. conclusions. These results provide a new basis for possible therapies to counteract retinitis pigmentosa and a new tool to characterize the mechanisms involved in the progress of retinal neurodegeneration.