Autophagy as an architect of embryogenesis: Understanding the new mechanisms, emerging paradigms, and future directions

Autophagy is no longer considered just a generic degradation pathway but is rather acknowledged as a programmed developmental mechanism whose roles in coordination across embryogenesis are still not very well understood. Various mammalian and non-mammalian models present evidence, where autophagy is switched on at fertilization, maintains proteostasis during cleavage, allocates lineage during blastocyst formation, and enforces genomic as well as cellular quality control by the selective removal of abnormal cells or paternal organelles. Moreover, following gastrulation, which gives rise to the germ layers, autophagy increasingly becomes a guiding factor for metabolic remodeling, differentiation, and morphogenesis within organs. Comparative analysis of the four essential organs i.e., liver, lung, heart, and brain's development, reveals that ATG5 is the only common autophagy gene involved in the process; while each of the organs also depend on additional, distinct regulators that are in line with its specific metabolic and morphogenetic needs. By integrating the roles of autophagy in early embryonic stages with its role at the organ level, this work offers a single conceptual framework of how autophagy coordinates developmental fidelity. At the same time, clinical evidence suggests that altered autophagy states may be associated with a variety of disorders such as those involving oocyte maturation, implantation, and placental homeostasis, thus giving developmental functions of autophagy, reproductive and physiological relevance. These revelations provide a conceptual basis for the understanding of congenital and tissue or organ-specific developmental ‍‌defects.