The autophagic machinery is necessary for removal of cell corpses from the developing retinal neuroepithelium.
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.
Mellén
M A
MA
Development, Differentiation & Degeneration Lab, Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maetzu 9, Madrid, Spain.
de la Rosa
E J
EJ
Boya
P
P
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D002642:Chick Embryo; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D010587:Phagocytosis / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism*; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology
D017304:Annexin A5; D010718:Phosphatidylserines; C025946:3-methyladenine; D000255:Adenosine Triphosphate; D000225:Adenine