Ambra1 regulates autophagy and development of the nervous system.
Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes. During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling. In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer; however, the roles of autophagy during embryonic development are still largely uncharacterized. Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality. Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro. Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.
Fimia
Gian Maria
GM
National Institute for Infectious Diseases, IRCCS L. Spallanzani, 00149 Rome, Italy.
Stoykova
Anastassia
A
Romagnoli
Alessandra
A
Giunta
Luigi
L
Di Bartolomeo
Sabrina
S
Nardacci
Roberta
R
Corazzari
Marco
M
Fuoco
Claudia
C
Ucar
Ahmet
A
Schwartz
Peter
P
Gruss
Peter
P
Piacentini
Mauro
M
Chowdhury
Kamal
K
Cecconi
Francesco
F
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C521754:Ambra1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D011506:Proteins