Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L, best known as NIX) at peak RGC differentiation. Retinas from NIX-deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. Similarly, we provide evidence that NIX-dependent mitophagy contributes to mitochondrial elimination during macrophage polarization towards the proinflammatory and more glycolytic M1 phenotype, but not to M2 macrophage differentiation, which primarily relies on oxidative phosphorylation. In summary, developmentally controlled mitophagy promotes a metabolic switch towards glycolysis, which in turn contributes to cellular differentiation in several distinct developmental contexts.

The primary function of the lens resides in its transparency and ability to focus light on the retina. These require both that the lens cells contain high concentrations of densely packed lens crystallins to maintain a refractive index constant over distances approximating the wavelength of the light to be transmitted, and a specific arrangement of anterior epithelial cells and arcuate fiber cells lacking organelles in the nucleus to avoid blocking transmission of light. Because cells in the lens nucleus have shed their organelles, lens crystallins have to last for the lifetime of the organism, and are specifically adapted to this function. The lens crystallins comprise two major families: the βγ-crystallins are among the most stable proteins known and the α-crystallins, which have a chaperone-like function. Other proteins and metabolic activities of the lens are primarily organized to protect the crystallins from damage over time and to maintain homeostasis of the lens cells. Membrane protein channels maintain osmotic and ionic balance across the lens, while the lens cytoskeleton provides for the specific shape of the lens cells, especially the fiber cells of the nucleus. Perhaps most importantly, a large part of the metabolic activity in the lens is directed toward maintaining a reduced state, which shelters the lens crystallins and other cellular components from damage from UV light and oxidative stress. Finally, the energy requirements of the lens are met largely by glycolysis and the pentose phosphate pathway, perhaps in response to the avascular nature of the lens. Together, all these systems cooperate to maintain lens transparency over time.

During embryonic development, the fibroblast growth factor (FGF) 3 signal transduction pathway regulates a range of cellular processes including cell proliferation, survival, migration, and differentiation (1). The mammalian FGF signaling is mediated by the interaction of specific secreted FGFs (i.e. FGF1 to FGF10) that work in conjunction with a specialized class of transmembrane receptor tyrosine kinases, the FGF receptors (FGFR1 to FGFR4). Formation of a complex between the dimeric FGFR and its FGF ligand dimer triggers a cascade of intracellular processes relayed by mitogen-activated kinases (MAPKs) such as Erk1 (official gene name: Mapk3) and Erk2 (Mapk1), PI-3/Akt kinase system, and other kinases. Upon entering the nucleus, Erk1/2 kinases elicit transcription of specific DNA-binding transcription factors and/or their post-translational modifications. While the majority of FGF signaling output includes activation of cell proliferation, survival, and motility, FGF signaling also regulates lens, myoblast, and osteogenic terminal differentiation (1, 2).The ocular lens has served as an advantageous model for studies of FGF signaling over many years (2). Primary rodent lens cell culture experiments showed that addition of a "high" concentration of bFGF/FGF2 (40 ng/ml) alone induced lens fiber cell terminal differentiation while "low" (0.15 ng/ml) and moderate (3 ng/ml) concentrations control cell survival and migration, respectively (3-5). FGF signaling is also modulated by the lens capsule, an extracellular matrix serving as an interface between the lens, aqueous and vitreous humor (6, 7). Subsequent genetic studies of FGF receptors (8, 9), components of the Frs2␣/Ras/MAPK signaling arm (10 -13), and the cooperating heparan sulfate biosynthesis pathway (14, 15) demonstrated in vivo roles of FGF signaling in mouse lens fiber cell survival and differentiation, and identified a set of lens regulatory genes, including c-Maf, Prox1, Etv1 (ER81), and Etv5 (ERM), whose expression was attenuated following genetic disruption of the FGF signaling pathway (9,14,15).Among these factors, Etv1 and Etv5 are well-established nuclear components of FGF signaling during neural development (16). The bZIP nuclear oncogene c-Maf encodes an important DNA-binding transcription factor that controls lens fiber cell differentiation through crystallin target genes (17). In addition to the lens, c-Maf regulates T-cell (18) and chondrocyte differentiation (19). Up-regulation of MAF was found in multiple myeloma cells and is a potential therapeutic target to treat this cancer (20). Therefore, a thorough understanding of c-Maf transcriptional control relates not only to the basic question of embryonic development but also for dysregulated gene expression during oncogenesis.