Abstract Changes in microglial cell activation and distribution are associated with neuronal decline the central nervous system (CNS), particularly under pathological conditions. Activated microglia converge on initial site of axonal degeneration human glaucoma, yet their part its pathophysiology remains unresolved. To begin with, it is unknown whether precedes or a late consequence retinal ganglion (RGC) neurodegeneration. Here we address this critical element DBA/2J (D2) mice, an...

purpose. In the context of retinal ganglion cell (RGC) axon degeneration in optic nerve that occurs glaucoma, microglia become activated, then phagocytic, and redistribute head. The authors investigated potential contribution activation to glaucoma progression DBA/2J chronic mouse model. methods. treated 6-week-old mice for 25 weeks with minocycline, a tetracycline derivative known reduce improve neuronal survival other models neurodegenerative disease. They quantified RGC numbers...

Glaucoma is a neurodegenerative disease that results in the progressive decline and ultimate death of retinal ganglion cells (RGCs). While multiple risk factors are associated with glaucoma, mechanisms leading to onset progression remain unknown. Molecular analysis various glaucoma models has revealed involvement non-neuronal cell populations, including astrocytes, Mueller glia microglia, at early stages glaucoma. High-dose irradiation was reported have significant long-term protective...

Microglia serve key homeostatic roles, and respond to neuronal perturbation decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis microglia activation, which begin at early stages the disease. However, possibility using live monitoring during disease progression predict severity neurodegeneration has not been explored. Because retina allows tracking fluorescent in their intact niche, here we investigated changes...

Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve retinal damage glaucoma preceded by local upregulation activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because signals through three pathways that intersect at C3 here we targeted step to restore balance glaucomatous retina determine its contribution degeneration onset and/or progression. To achieve...

Microglia serve critical remodeling roles that shape the developing nervous system, responding to changing neural environment with phagocytosis or soluble factor secretion. Recent single-cell sequencing (scRNAseq) studies have revealed context-dependent diversity in microglial properties and gene expression, but cues promoting this are not well defined. Here, we ask how interactions apoptotic neurons state, including lysosomal lipid metabolism expression dependence on Colony-stimulating 1...

During development of the retina, programmed cell death helps to establish final size and distribution various classes in distinct layers tissue. Here we show that dying cells developing ganglion inner nuclear are clustered spatially gap junction inhibitors decrease clustering cells. To confirm role junctions death, induced targeted via intracellular cytochrome c (C ) examined their neighbors for apoptotic morphology or caspase-3 cleavage. These studies indicate bystander killing extends...

Microglia have important remodeling functions in neurodevelopment, aging, and disease, with evidence for molecular diversity. However, the signaling pathways environmental cues that drive diverse states of microglia are incompletely understood. We profiled a discrete developing CNS region, murine retina. found distinct transcriptional signatures retinal across development peak postnatal density population resembles aging disease-associated (DAM) CD11c

Abstract Glaucoma is a leading cause of blindness, characterized by retinal ganglion cell ( RGC ) loss and optic nerve ON damage. Cumulative evidence suggests glial involvement in the degeneration s. We analyzed contribution microglial reactivity to early axoglial alterations an induced model ocular hypertension. For this purpose, vehicle or chondroitin sulfate CS were weekly injected into eye anterior chamber from Wistar rats for different intervals. The amount Brn3a(+) significantly...

ABSTRACT Microglia, the parenchymal macrophage of central nervous system, serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these are, cues promote them, or they impact function. In developing retina, we previously found a significant proportion microglia express CD11c (Integrin αX, Itgax, subunit complement receptor 4) which...

Retinal ganglion cells (RGCs) are the projection neurons of retina, and their death promotes an irreversible blindness. Several factors were described to control genesis during retinal development which include Atoh7 as a major orchestrator for RGC program downstream targets, including Pou4f factors, in turn regulate key aspects terminal differentiation. The absence POU4F family genes results defects differentiation, aberrant axonal elaboration ultimately death, confirming requirement...

Scaffolding of membrane proteins is a common strategy for forming complexes proteins, including some connexins, within microdomains. Here we describe studies indicating that Cx32 interacts with PDZ-containing scaffolding protein, Dlgh1 (Discs Large homolog 1). Initial screens liver lysates using antibody arrays indicated an interaction between and was confirmed coimmunoprecipitation studies. Yeast two-hybrid complementation determined the bound via SH3/Hook domain Dlgh1. Confocal microscopy...

Microglia, the parenchymal macrophage of central nervous system serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these are, cues promote them, or they impact function. In developing retina, we previously found a significant proportion microglia express CD11c (Integrin αX, complement receptor 4,

Neurodegeneration in glaucoma results decline and loss of retinal ganglion cells (RGCs), is associated with activation myeloid such as microglia macrophages. The chemokine fractalkine (FKN or Cx3cl1) mediates communication from neurons to cells. Signaling through its receptor Cx3cr1 has been implicated multiple neurodegenerative diseases, but the effects on neuronal pathology are variable. Since it unknown how FKN-mediated crosstalk influences RGC degeneration glaucoma, we assessed this a...

We show here that neurite outgrowth of ganglion cells (RGCs) was selectively enhanced following treatment with BDNF or NT-4 in short-term cultures dissociated derived from the neuroretina postnatal rats. more effective than BDNF. The effect NT-3 variable, whereas NGF and CNTF had no effects upon elongation. neuritogenic responses RGCs to both were prevented by competition soluble TrkB receptor, abolished K252a, a selective inhibitor tyrosine kinase activity Trks. These results indicate...

Microglia, which are CNS-resident neuroimmune cells, transform their morphology and size in response to CNS damage, switching an activated state with distinct functions gene expression profiles. The roles of microglial activation health, injury disease remain incompletely understood due dynamic complex regulation changes microenvironment. Thus, it is critical non-invasively monitor analyze over time the intact organism. In vivo studies have been delayed by technical limitations tracking...

Retinal development follows a conserved neurogenic program in vertebrates to orchestrate the generation of specific cell types from multipotent progenitors sequential but overlapping waves. In this program, retinal ganglion cells (RGCs) are first type generated. RGCs final output neurons retina and essential for vision circadian rhythm. Key molecular steps have been defined multiple vertebrate species regulate competence, specification, terminal differentiation type. This involves...

In adult retina, aquaporin-4 (AQP4) and inwardly rectifying K(+) (Kir4.1) channels localize to astrocyte Müller cell membranes facing vascular vitreous compartments, optimizing clearance of extracellular water from the synaptic layers. However, it is unknown whether these are expressed at early developmental stages, before gliogenesis or angiogenesis take place in neural retina. This study was conducted determine presence AQP4 Kir4.1 proteins developing mouse retina.Simultaneous...

Abstract Changes in microglial cell activation and distribution are associated with neuronal decline the central nervous system (CNS), particularly under pathological conditions. Activated microglia converge on initial site of axonal degeneration human glaucoma, yet their part its pathophysiology remains unresolved. To begin with, it is unknown whether precedes or a late consequence retinal ganglion (RGC) neurodegeneration. Here we address this critical element DBA/2J (D2) mice, an...

ABSTRACT Retinal ganglion cells (RGCs) are the projection neurons of retina. In early retinal progenitor (RPCs), Atoh7 orchestrates developmental RGC program and regulates expression critical downstream targets, including Pou4f factors. The absence Pou4f2 or more POU4F family genes results in defects differentiation, aberrant axonal elaboration ultimately death, confirming requirement factors for development survival, with a role regulating axon outgrowth pathfinding. Here, we investigated...