A novel role for autophagy in neurodevelopment.
We recently showed that Ambra 1, a WD40-containing approximately 130 KDa protein, is a novel activating molecule in Beclin 1-regulated autophagy and plays a role in the development of the nervous system. Ambra 1 binds to Beclin 1 and favors Beclin 1/Vps34 interaction. At variance with these factors, Ambra 1 is highly conserved among vertebrates only, and its expression is mostly confined to the neuroepithelium during early neurogenesis. Ambra 1 functional inactivation in mouse led to lethality in utero (starting from embryonic day 14.5), characterized by severe neural tube defects associated with autophagy impairment, unbalanced cell proliferation, accumulation of ubiquitinated proteins, and excessive apoptosis. We also demonstrated that hyperproliferation was the earliest detectable abnormality in the developing neuroepithelium, followed by a wave of caspase-dependent cell death. These findings provided in vivo evidence supporting the existence of a complex interplay between autophagy, cell proliferation and cell death during neural development in mammals. In this article, we review our findings in the contexts of autophagy and neurodevelopment and consider some of the issues raised.
Cecconi
Francesco
F
Dulbecco Telethon Institute at the Department of Biology, University of Rome Tor Vergata, Rome, Italy. fcecconi@dti.telethon.it
Di Bartolomeo
Sabrina
S
Nardacci
Roberta
R
Fuoco
Claudia
C
Corazzari
Marco
M
Giunta
Luigi
L
Romagnoli
Alessandra
A
Stoykova
Anastassia
A
Chowdhury
Kamal
K
Fimia
Gian Maria
GM
Piacentini
Mauro
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D005260:Female; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009420:Nervous System / Q000196:embryology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011247:Pregnancy; D011506:Proteins / Q000502:physiology
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; D019869:Phosphatidylinositol 3-Kinases