During development, autophagy also is associated with the structural remodeling of cells. It is enhanced under conditions of stress like starvation, hypoxia, and various pathological conditions. 4 - 6 Autophagy, a highly regulated process, occurs at basal levels in all cells to mediate protein and organelle turnover to meet the cells’ energy demands. 5, 15, 16 Autophagosomes fuse with lysosomes that degrade their cargo and return amino acids and recycled cellular components to the cell. Molecules such as Atg1/ULK1, class III phosphatidylinositol 3-kinase (PtdIns3K), Vps34/PIK3C3 (phosphatidylinositol 3-kinase, catalytic subunit type 3) and Vps30/BECN1 can induce autophagosome formation and a subset of these molecules, along with others like MAP1LC3B (microtubule-associated protein 1 light chain 3 β)/LC3B, are important to both the elongation and maturation of the autophagosome. 7, 13, 14 Little is known about the signaling mechanisms that initiate autophagy-dependent differentiation pathways.Īutophagy is a catabolic process that begins as the phagophore, which forms at the phagophore assembly site, extends around cytoplasmic cargo such as proteins and organelles and then fuses to form the autophagosome, a double-membraned vesicle that completely surrounds its cargo. 12 Most of our knowledge of how autophagy functions in regulating cell differentiation is based on tissue specific knockouts of autophagy-related genes.
3, 4 The autophagy process also plays an essential role in tissue development, 5, 6 and cell differentiation including that of reticulocytes, 7, 8 B cells, 9 macrophages, 10 adipocytes, 11 and osteoclasts. These results reveal that MAPK/JNK is a positive regulator of MTORC1 signaling and its developmentally regulated inactivation provides an inducing signal for the coordinated autophagic removal of nuclei and organelles required for lens function.Īutophagy, initially known as a form of cell death 1, 2 is now understood to be involved in regulating cell survival, cellular homeostasis, and physiological function. Autophagy pathway proteins including ULK1, BECN1/Beclin 1, and MAP1LC3B2/LC3B-II were upregulated in the presence of inhibitors to either MAPK/JNK or MTOR, inducing autophagic loss of organelles to form the OFZ. Here, we report our discovery that inactivation of MAPK/JNK induces autophagy for formation of the OFZ through its regulation of MTORC1, where MAPK/JNK signaling is required for both MTOR activation and RPTOR/RAPTOR phosphorylation. To address these questions we studied the ocular lens, as the programmed elimination of nuclei and organelles occurs in a precisely regulated spatiotemporal manner to form the organelle-free zone (OFZ), a characteristic essential for vision acuity. Although autophagic pathways are essential to developmental processes, many questions still remain regarding the initiation signals that regulate autophagy in the context of differentiation.