Glial Purinergic Signals and Psychiatric Disorders

Emotion-related neural networks are regulated in part by the activity of glial cells, and glial dysfunction can be directly related to emotional diseases such as depression. Here, we discuss three different therapeutic strategies involving astrocytes that are effective for treating depression. First, the antidepressant, fluoxetine, acts on astrocytes and increases exocytosis of ATP. This has therapeutic effects via brain-derived neurotrophic factor-dependent mechanisms. Second, electroconvulsive therapy is a well-known treatment for drug-resistant depression. Electroconvulsive therapy releases ATP from astrocytes to induce leukemia inhibitory factors and fibroblast growth factor 2, which leads to antidepressive actions. Finally, sleep deprivation therapy is well-known to cause antidepressive effects. Sleep deprivation also increases release of ATP, whose metabolite, adenosine, has antidepressive effects. These independent treatments share the same mechanism, i.e., ATP release from astrocytes, indicating an essential role of glial purinergic signals in the pathogenesis of depression.

Molecular and Clinical Significance of Fibroblast Growth Factor 2 in Development and Regeneration of the Auditory System

The fibroblast growth factor 2 (FGF2) is a member of the FGF family which is involved in key biological processes including development, cellular proliferation, wound healing, and angiogenesis. Although the utility of the FGF family as therapeutic agents has attracted attention, and FGF2 has been studied in several clinical contexts, there remains an incomplete understanding of the molecular and clinical function of FGF2 in the auditory system. In this review, we highlight the role of FGF2 in inner ear development and hearing protection and present relevant clinical studies for tympanic membrane (TM) repair. We conclude by discussing the future implications of FGF2 as a potential therapeutic agent.

Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2

Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is transported into the extracellular space by an unconventional secretory mechanism. Cell surface heparan sulfate proteoglycans are known to play an essential role in this process. Unexpectedly, we found that among the diverse sub-classes consisting of syndecans, perlecans, glypicans and others, Glypican-1 (GPC1) is both the principle and rate-limiting factor that drives unconventional secretion of FGF2. By contrast, we demonstrate GPC1 to be dispensable for FGF2 signaling into cells. We provide first insights into the structural basis for GPC1-dependent FGF2 secretion, identifying disaccharides with N-linked sulfate groups to be enriched in the heparan sulfate chains of GPC1 to which FGF2 binds with high affinity. Our findings have broad implications for the role of GPC1 as a key molecule in tumor progression.

YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2

Ocular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms remain largely unknown. Here, we report that lactylation in microglia is critical for retinal neovascularization. Using lactylome and proteomic analyses, we identified a list of hyperlactylated proteins in the context of increased lactate under hypoxia. Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183) under hypoxia, which is regulated by p300. Furthermore, hyperlactylated YY1 directly enhances fibroblast growth factor 2 (FGF2) transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Notably, clinical retrospective analysis shows that lactate concentrations in retinopathy of prematurity (ROP) infants are significantly increased compared with those in controls. Taken together, our results demonstrate that YY1 lactylation in microglia promotes FGF2 expression and plays a pivotal proangiogenic role, providing new insights into retinal neovascular diseases.