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Recent studies have demonstrated that insulin can have profound affects on the survival of neurons within the retina. The purpose of this study was to determine how insulin‐like growth factor 1 (IGF1) influences retinal cells; in particular, the glial cells. We identify a novel type of glial cell in the avian retina and provide evidence that these cells can respond to acute damage and IGF1. In normal...
High blood ammonia, elevated glutamine, and hyponatremia are pathogenic factors contributing to astrocytic swelling and brain edema in liver failure. We investigated the effects of hypoosmolarity, ammonia, and glutamine on the induction of glial cell swelling in freshly isolated slices of the rat retina. Glutamine, but not ammonia or hypoosmolarity per se, evoked a rapid (within one minute) swelling...
In lower vertebrates, such as fish, Müller glia plays an essential role in the restoration of visual function after retinal degeneration by transdifferentiating into photoreceptors and other retinal neurons. During this process, Müller cells re‐enter the cell cycle, proliferate, and migrate from the inner nuclear layer (INL) to the photoreceptor layer where they express photoreceptor‐specific markers...
Müller glia are the resident radial glia in the vertebrate retina. The response of mammalian Müller glia to retinal damage often results in a glial scar and no functional replacement of lost neurons. Adult zebrafish Müller glia, in contrast, are considered tissue‐specific stem cells that can self‐renew and generate neurogenic progenitors to regenerate all retinal neurons after damage. Here, we demonstrate...
MPP3 and CRB1 both interact directly with PALS1/MPP5 and through this scaffold protein may form a large protein complex. To investigate the role of MPP3 in the retina we have analyzed conditional mutant Mpp3 knockout mice. Ultrastructural localization studies revealed that MPP3 is predominantly localized in apical villi of Müller glia cells. Retinas lacking MPP3 developed late onset retinal degeneration,...
In retinas where Müller glia have been stimulated to become progenitor cells, reactive microglia are always present. Thus, we investigated how the activation or ablation of microglia/macrophage influences the formation of Müller glia‐derived progenitor cells (MGPCs) in the retina in vivo. Intraocular injections of the Interleukin‐6 (IL6) stimulated the reactivity of microglia/macrophage, whereas other...
Reactive microglia and macrophages are prevalent in damaged retinas. Accordingly, we investigate how the activation or ablation of microglia/macrophages influences the survival of neurons in the chick retina in vivo. We applied intraocular injections of interleukin 6 (IL6) to stimulate the reactivity of microglia/macrophages and clodronate‐liposomes to ablate microglia/macrophages. Activation of the...
Neuroepithelial and radial GLIA stem cells generate the majority of the cellular constituents of the central nervous system. Following precisely timed phases of neurogenesis and gliogenesis the stem cells recede, with the exception of adult neural stem cells that persist in two generally accepted canonical neurogenic regions, the subventricular zone of the lateral ventricle and the subgranular zone...
Retinal gliosis is characterized by biochemical and physiological changes that often lead to Müller glia proliferation and hypertrophy and is a feature of many neuro‐degenerative and inflammatory diseases such as proliferative vitreoretinopathy (PVR). Although Müller glia are known to release inflammatory factors and cytokines, it is not clear whether cytokine production by these cells mirrors the...
Reactive gliosis is an umbrella term for various glia functions in neurodegenerative diseases and upon injury. Specifically, Müller glia (MG) in some species readily regenerate retinal neurons to restore vision loss after insult, whereas mammalian MG respond by reactive gliosis—a heterogeneous response which frequently includes cell hypertrophy and proliferation. Limited regeneration has been stimulated...
A striking aspect of tissue regeneration is its uneven distribution among different animal classes, both in terms of modalities and efficiency. The retina does not escape the rule, exhibiting extraordinary self‐repair properties in anamniote species but extremely limited ones in mammals. Among cellular sources prone to contribute to retinal regeneration are Müller glial cells, which in teleosts have...
Cell shape is critical for the proper function of every cell in every tissue in the body. This is especially true for the highly morphologically diverse neural and glia cells of the central nervous system. The molecular processes by which these, or indeed any, cells gain their particular cell‐specific morphology remain largely unexplored. To identify the genes involved in the morphogenesis of the...
Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation‐induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is...
The human retina contains three types of glial cells: microglia and two types of macroglia, astrocytes and Müller cells. Macroglia provide homeostatic and metabolic support to photoreceptors and neurons required for neuronal activity. The fovea, the site of the sharpest vision which is astrocyte‐ and microglia‐free, contains two populations of Müller glia: cells which form the Müller cell cone in...
Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp‐9), during this regenerative neurogenesis. Following photoreceptor ablation, anti‐inflammatory...
Damage to the zebrafish retina stimulates resident Müller glia to reprogram, reenter the cell cycle, divide asymmetrically, and produce neuronal progenitor cells that amplify and differentiate into the lost neurons. The transition from quiescent to proliferative Müller glia involves both positive and negative regulators. We previously demonstrated that the Notch signaling pathway represses retinal...
Recent studies suggest midkine (MDK) is involved in the development and regeneration of the zebrafish retina. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia‐derived progenitor cells (MGPCs) in chick and mouse model systems. By using single‐cell RNA‐sequencing, we find that MDK and pleiotrophin (PTN), a...
Neurodegenerative disorders, characterized by progressive neuronal loss, eventually lead to functional impairment in the adult mammalian central nervous system (CNS). Importantly, these deteriorations are irreversible, due to the very limited regenerative potential of these CNS neurons. Stimulating and redirecting neuroinflammation was recently put forward as an important approach to induce axonal...
The importance of Müller glia for retinal homeostasis suggests that they may have vulnerabilities that lead to retinal disease. Here, we studied the effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health. Immunostaining indicated that murine Müller glia expressed insulin receptor (IR), hexokinase 2 (HK2) and phosphoglycerate dehydrogenase (PHGDH) but very little...
Endocannabinoids (eCB) are lipid‐based neurotransmitters that are known to influence synaptic function in the visual system. eCBs are also known to suppress neuroinflammation in different pathological states. However, nothing is known about the roles of the eCB system during the transition of Müller glia (MG) into proliferating progenitor‐like cells in the retina. Accordingly, we used the chick and...
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