Ambra1 regulates autophagy and development of the nervous system

Abstract

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.

Autophagy in Cell Life and Cell Death

“…Other Atg knockout neonates, such as Atg3 (Sou et al, 2008), Atg7 (Komatsu et al, 2005), Atg9 (Saitoh et al, 2009), and Atg16L1 (Saitoh et al, 2008), also die shortly after birth. In contrast with the embryonic survival seen with these knockout mice, knockout of other autophagy genes such as beclin 1, Ambra1, and FIP200 produce other phenotypes (Fimia et al, 2007;Gan et al, 2006;Yue, Jin, Yang, Levine, & Heintz, 2003), presumably because of additional roles that these proteins play, such as regulation of endocytosis (Mizushima & Levine, 2010;Ruck et al, 2011).…”

“…Ulk1 is also critical for axon outgrowth and differentiation of neurons (Tomoda, Bhatt, Kuroyanagi, Shirasawa, & Hatten, 1999). Ambra1 knockout causes early lethality in mice and also leads to pronounced defects in the central nervous system, such as neural tube closure defects and exencephaly (Fimia et al, 2007). In the heart, Atg5 deficiency results in cardiac dysfunction in adult mice (Tomoda et al, 1999).…”

Beneficial Bacteria Affect Danio rerio Development by the Modulation of Maternal Factors Involved in Autophagic, Apoptotic and Dorsalizing Processes

“…This hypothesis was not supported by the results here obtained. Even though autophagy was recognized as a process of pivotal importance [42], its regulating genes, which have been described by numerous studies [43,44,45,46], were found to be less expressed in the embryos of the PROBIO group than in controls. We could therefore speculate that some fundamental, yet unknown, process influencing the amount of both autophagic and apoptotic messages has happened during oogenesis at class V zebrafish oocytes.…”

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

“…Several studies using mice deficient for autophagy-related genes have outlined the importance of the autophagic machinery in embryonic development of the CNS [233][234][235][236]. In particular, autophagy is necessary for proper neuronal differentiation [237,238].…”