Autophagy Gene-Dependent Clearance of Apoptotic Cells during Embryonic Development

Cell 128, 931-946 (2007)

Speaker: 蔡志文                                                     Time: 15:10-16:00, April 11, 2007

Commentator: 王耀賢 博士                                  Place: Room 601

Abstract:

Autophagy is a conserved lysosomal-mediated degradation process involved in the turnover of long-lived proteins and organelles.  In response to nutrient deprivation, autophagy has been suggested to help cell survival (1).  Autophagy is highly active in developmental processes that involve massive cell elimination (2).  In such cases, autophagy has been assumed a form of programmed cell death (PCD), but its function in dying cells during development remains unclear.  In mammalian development, the first wave of PCD occurs during cavitation of the early embryo. To mimic early embryogenesis in vitro, mouse embryonic stem (ES) cells were used in this study to examine the role of autophagy in developmental PCD.  The ES cells form undifferentiated cell aggregates in cultures that develop into simple embryoid bodies (EBs), containing an outer layer of endodermal cells and an inner solid core of ectodermal cells.  The inner ectodermal cells of the simple EBs undergo PCD to form cystic EBs.  The authors found that autophagy was active during the embryonic development.  EBs derived from cells lacking the autophagy genes, atg5 orbeclin1, expressed normal cavitation signals, visceral endoderm differentiation, and apoptotic cell death, but displayed a defect in formation of cavitated EBs.  Apoptotic cell clearance is critical incavitation.  The atg5^-/- and beclin1^-/- EBs showed apoptotic corpse engulfment defect.  Dying cells in autophagy gene null EBs failed to generate the “eat-me” signal of phosphatidylserine exposure and the “come-get-me” signal, lysophosphatidylcholine.  Interestingly, atg5^-/- and beclin1^-/- EB cells showed decreased ATP production, and the defects in cavitation was reversed by the treatment of tricarboxylic acid substrate, methylpyruvate.  Together, autophagy provided the energy to help generating the clearance signals of apoptotic cells in morphogenesis during development.

References:

1.      Meijer, A.J. et al. Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445-2462 (2004).

2.      Jacobson, M.D., Weil, M., and Raff, M.C. Programmed cell death in animal development. Cell 88, 347-354. (1997)