Clearance phagocytosis is a documented function of Müller glia in the retina. However, the molecular mechanisms of Müller glia phagocytosis remain largely undefined. Here, we show that extracellular galectin-3 and protein S promote clearance phagocytosis by immortalized human MIO-M1 Müller cells in an additive, saturable manner. Galectin-3 promotes phagocytosis by primary Müller glia from wild-type (WT) mice but not from mice that lack the engulfment receptor MERTK and therefore develop postnatal photoreceptor degeneration. Probing a possible functional link between Müller galectin-3 and MERTK, we discovered that mertk−/− Müller glia in situ show excess galectin-3 at postnatal day 20 (P20), an age prior to detectable photoreceptor degeneration. Moreover, double knockout (DKO) mice lacking both galectin-3 and MERTK show increased activation of Müller cells (but not of microglia) at P20 and more pronounced photoreceptor loss at P35 compared to mice lacking MERTK alone. Exploring the well-established sodium iodate injury model, we also found more severe activation specifically of Müller glia, and worse retinal damage in mice lacking galectin-3 compared to WT mice. Indeed, galectin-3 deficiency significantly increased sensitivity to injury, yielding Müller activation and retinal damage at a sodium iodate concentration that had no effect on the WT retina. Altogether, our results from both inherited and acutely induced models of retinal degeneration agree that eliminating galectin-3 exacerbates Müller cell activation and retinal degeneration. These data identify an important protective role for the MERTK ligand galectin-3 in the retina in restraining Müller glia activation.
Most populations live in spatially structured environments and that structure has the potential to impact the evolutionary dynamics in a number of important ways. Theoretical models tracking evolution in structured environments using a range of different approaches, suggest that local interactions and spatial heterogeneity can increase the adaptive benefits of motility, impact both the rate and extent of adaptation, and increase the probability of parallel evolution. We test these general predictions in a microbial evolution experiment tracking phenotypic and genomic changes in replicate populations of Pseudomonas fluorescens evolved in both well-mixed and spatially-structured environments, where spatial structure was generated through the addition of semi-solid agar. In contrast to the well-mixed environment, populations evolved in the spatially-structured environment adapted more slowly, retained the ability to disperse more rapidly, and had a greater putatively neutral population genomic diversity. The degree of parallel evolution measured at the gene-level, did not differ across these two types of experimental environments, perhaps because the populations had not evolved for long enough to near their fitness optima. These results confirm important general impacts of spatial structure on evolutionary dynamics at both the phenotypic and genomic level.
During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression. Rewiring the cellular proteome shifts the phenotypic balance between growth and adaptation to promote therapeutic resistance and cancer cell survival. The integrated stress response (ISR) is a key translational program activated by oncogenic stress that is utilized to fine-tune protein synthesis and adjust to environmental barriers. Here, we focus on the role of ISR signaling for driving cancer progression. We highlight mechanisms of regulation for distinct mRNA translation downstream of the ISR, expand on oncogenic signaling utilizing the ISR in response to environmental stresses, and pinpoint the impact this has for cancer cell plasticity during resistance to therapy. There is an ongoing need for innovative drug targets in cancer treatment, and modulating ISR activity may provide a unique avenue for clinical benefit.
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