Autophagy in mammalian development and differentiation

Abstract

It has been known for many decades that autophagy, a conserved lysosomal degradation pathway, is highly active during differentiation and development. However, until the discovery of the autophagy-related (ATG) genes in the 1990s, the functional significance of this activity was unknown. Initially, genetic knockout studies of ATG genes in lower eukaryotes revealed an essential role for the autophagy pathway in differentiation and development. In recent years, the analyses of systemic and tissue-specific knockout models of ATG genes in mice has led to an explosion of knowledge about the functions of autophagy in mammalian development and differentiation. Here we review the main advances in our understanding of these functions.

Figure 1

Representative images of the induction of autophagy and the outcome of its suppression. (a) Electron microscopic analysis of mouse embryonic fibroblasts during nutrient starvation. Mitochondria (m) and fragments of endoplasmic reticulum (e) are observed inside an autophagosome (arrow). Mitochondria may be randomly sequestered under conditions of starvation, but can be selectively degraded during erythroid differentiation and Parkin-mediated mitophagy. Scale bar, 500 nm. (b) Induction of autophagy after fertilization. Unfertilized (left) and fertilized (right) oocytes from female mice expressing GFP–LC3 to monitor autophagosome formation were observed by confocal microscopy. Small dots indicate GFP–LC3-positive autophagosomes. Scale bar, 10 µm. (c) Accumulation of ubiquitin-positive inclusion bodies in neurons of Atg5-deficient mice. Dorsal root ganglion neurons from wild-type (left) and systemic Atg5-deficient (right) neonates were stained with a monoclonal anti-ubiquitin antibody (1B3, purchased from MBL). Scale bar, 10 µm.

Figure 2

The role of autophagy in development and differentiation in mammals. Autophagy has critical roles in fertilized oocytes and neonates through protein catabolism and the resulting production of the necessary amino acids. Autophagy is also important in cell remodelling (for example in mitochondrial elimination) during the differentiation of erythrocytes, lymphocytes and adipocytes. Finally, the role of autophagy in housekeeping is important, particularly in terminally differentiated cells such as neurons and hepatocytes, in which continuous renewal of cytoplasmic contents is essential.