Autophagy is a homoeostatic process necessary for the clearance of damaged or superfluous proteins and organelles. The recycling of intracellular constituents also provides energy during periods of metabolic stress, thereby contributing to cell viability. In addition, disruption of autophagic machinery interferes with embryonic development in several species, although the underlying cellular processes affected remain unclear. Here, we investigate the role of autophagy during the early stages of chick retina development, when the retinal neuroepithelium proliferates and starts to generate the first neurons, the retinal ganglion cells. These two developmental processes are accompanied by programmed cell death. Upon treatment with the autophagic inhibitor 3-methyladenine, retinas accumulated numerous TdT-mediated dUTP nick-end labelling-positive cells that correlated with a lack of the 'eat-me' signal phosphatidylserine (PS). In consequence, neighbouring cells did not engulf apoptotic bodies and they persisted as individual cell corpses, a phenotype that was also observed after blockade of phagocytosis with phospho-L-Serine. Supplying the retinas with methylpyruvate, a cell-permeable substrate for ATP production, restored ATP levels and the presentation of PS at the cell surface. Hence, engulfment and lysosomal degradation of apoptotic bodies were also re-established. Together, these data point to a novel role for the autophagic machinery during the development of the central nervous system.

Programmed cell death, together with proliferation and differentiation, is an essential process during the development of the nervous system. During neurogenesis, neurons and glia are generated in large numbers and, subsequently, they die in a process that depends on trophic signalling that refines the cytoarchitecture and connectivity of the nervous system. In addition, programmed cell death also affects proliferating neuroepithelial cells and recently differentiated neuroblasts. Autophagy is a lysosomal degradative pathway that allows the recycling of cell constituents, and seems to be able to play a dual role. It may serve to protect the cell by preventing the accumulation of deleterious products and organelles and supplying energy and amino acids. On the other hand, it has been considered a type of cell death. The role of autophagy during development is little characterized. The retina provides an excellent model system to study autophagy in the context of neural development, and to establish its relationship with proliferation, differentiation and cell death. In the present review, we summarize recent findings showing that autophagy contributes to the development of the nervous system by providing energy for cell corpse removal after physiological cell death, a process associated with retinal neurogenesis.

Apoptosis and autophagy are physiological processes implicated in the maintenance of cell and tissue homeostasis. We took advantage of the existence of multiple phases of developmental cell death in the embryonic chick retina and of the availability of short-term organotypic retinal cultures to explore the possible relationship between apoptosis and autophagy during neural development. We examined retinas at embryonic day 5, an early stage at which cell death is related to eye morphogenesis and to retinal ganglion cell generation, as well as at embryonic day 9, when cell death is associated with neurotrophic support of the retinal ganglion cells. Exposure to 3-methyl-adenine, a classical inhibitor of autophagy, elicited a selective accumulation of apoptotic bodies in the dorsotemporal area of embryonic day 5 retinas where neurogenesis is taking place. This accumulation was correlated with a blockage of phosphatidyl-serine presentation and, consequently, with a lack of engulfment of the dying cells by their neighbors. In striking contrast, none of these phenomena were observed in association with cell death in the optic nerve and optic fissure at embryonic day 5, or in embryonic day 9 retinas. Our data suggest that autophagy is essential for phosphatidyl-serine presentation by apoptotic cells during the phase of cell death associated to neurogenesis, but this is not a universal requirement for all phases of cell death occurring during retinal development.