Targeted deletion of Vegfa in adult mice induces vision loss

Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.

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SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

10.1101/2020.04.30.069385 ◽

2020 ◽

Author(s):

Yo Sasaki ◽

Hiroki Kakita ◽

Shunsuke Kubota ◽

Abdoulaye Sene ◽

Tae Jun Lee ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Vision Loss ◽

Adult Mice ◽

Conditional Deletion ◽

Cell Death Pathway ◽

Human Pathology ◽

Essential Function ◽

Photoreceptor Death

AbstractLeber congenital amaurosis type 9 is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

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SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

eLife ◽

10.7554/elife.62027 ◽

2020 ◽

Vol 9 ◽

Author(s):

Yo Sasaki ◽

Hiroki Kakita ◽

Shunsuke Kubota ◽

Abdoulaye Sene ◽

Tae Jun Lee ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Vision Loss ◽

Adult Mice ◽

Conditional Deletion ◽

Cell Death Pathway ◽

Human Pathology ◽

Essential Function ◽

Photoreceptor Death

Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

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CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity

International Journal of Molecular Sciences ◽

10.3390/ijms20174069 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4069 ◽

Cited By ~ 7

Author(s):

C. Henrique Alves ◽

Nanda Boon ◽

Aat A. Mulder ◽

Abraham J. Koster ◽

Carolina R. Jost ◽

...

Keyword(s):

Contrast Sensitivity ◽

Vision Loss ◽

Photoreceptor Cells ◽

Rod Photoreceptor ◽

Adult Mice ◽

Retinal Dystrophies ◽

Functional Consequences ◽

Rod Function ◽

Subapical Region ◽

Additional Loss

Variations in the Crumbs homolog-1 (CRB1) gene are associated with a wide variety of autosomal recessive retinal dystrophies, including early onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). CRB1 belongs to the Crumbs family, which in mammals includes CRB2 and CRB3. Here, we studied the specific roles of CRB2 in rod photoreceptor cells and whether ablation of CRB2 in rods exacerbates the Crb1-disease. Therefore, we assessed the morphological, retinal, and visual functional consequences of specific ablation of CRB2 from rods with or without concomitant loss of CRB1. Our data demonstrated that loss of CRB2 in mature rods resulted in RP. The retina showed gliosis and disruption of the subapical region and adherens junctions at the outer limiting membrane. Rods were lost at the peripheral and central superior retina, while gross retinal lamination was preserved. Rod function as measured by electroretinography was impaired in adult mice. Additional loss of CRB1 exacerbated the retinal phenotype leading to an early reduction of the dark-adapted rod photoreceptor a-wave and reduced contrast sensitivity from 3-months-of-age, as measured by optokinetic tracking reflex (OKT) behavior testing. The data suggest that CRB2 present in rods is required to prevent photoreceptor degeneration and vision loss.

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Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages

Journal of Experimental Medicine ◽

10.1084/jem.20121187 ◽

2013 ◽

Vol 210 (5) ◽

pp. 969-985 ◽

Cited By ~ 30

Author(s):

Riku Kiviranta ◽

Kei Yamana ◽

Hiroaki Saito ◽

Daniel K. Ho ◽

Julius Laine ◽

...

Keyword(s):

Bone Formation ◽

Transcriptional Activity ◽

Bone Homeostasis ◽

Targeted Deletion ◽

Bone Phenotype ◽

Adult Mice ◽

Transcriptional Coregulator ◽

Early B Cell Factor ◽

Coordinated Effects

Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521+/− mice was rescued in Zfp521+/−:Ebf1+/− mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis.

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Flexible cue anchoring strategies enable stable head direction coding in both sighted and blind animals

10.1101/2022.01.12.476111 ◽

2022 ◽

Author(s):

Kadjita Asumbisa ◽

Adrien Peyrache ◽

Stuart Trenholm

Keyword(s):

Vision Loss ◽

Spatial Information ◽

Sensory Information ◽

Olfactory Cues ◽

Navigation Systems ◽

Head Direction ◽

Dorsal Nucleus ◽

Adult Mice ◽

Congenitally Blind ◽

Neuronal Encoding

Vision plays a crucial role in instructing the brain's spatial navigation systems. However, little is known about how vision loss affects the neuronal encoding of spatial information. Here, recording from head direction (HD) cells in the anterior dorsal nucleus of the thalamus in mice, we find stable and robust HD tuning in blind animals. In contrast, placing sighted animals in darkness significantly impairs HD cell tuning. We find that blind mice use olfactory cues to maintain stable HD tuning and that prior visual experience leads to refined HD cell tuning in blind adult mice compared to congenitally blind animals. Finally, in the absence of both visual and olfactory cues, the HD attractor network remains intact but the preferred firing direction of HD cells continuously drifts over time. We thus demonstrate remarkable flexibility in how the brain uses diverse sensory information to generate a stable directional representation of space.

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SP-B deficiency causes respiratory failure in adult mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00011.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. L543-L549 ◽

Cited By ~ 93

Author(s):

Kristin R. Melton ◽

Lori L. Nesslein ◽

Machiko Ikegami ◽

Jay W. Tichelaar ◽

Jean C. Clark ◽

...

Keyword(s):

Respiratory Failure ◽

Lung Function ◽

Lavage Fluid ◽

Surfactant Protein ◽

Targeted Deletion ◽

Adult Mice ◽

Regulated Expression ◽

Surfactant Activity ◽

Surfactant Dysfunction

Targeted deletion of the surfactant protein (SP)-B locus in mice causes lethal neonatal respiratory distress. To assess the importance of SP-B for postnatal lung function, compound transgenic mice were generated in which the mouse SP-B cDNA was conditionally expressed under control of exogenous doxycycline in SP-B-/- mice. Doxycycline-regulated expression of SP-B fully corrected lung function in compound SP-B-/- mice and protected mice from respiratory failure at birth. Withdrawal of doxycycline from adult compound SP-B-/- mice resulted in decreased alveolar content of SP-B, causing respiratory failure when SP-B concentration was reduced to <25% of normal levels. Decreased SP-B was associated with low alveolar content of phosphatidylglycerol, accumulation of misprocessed SP-C proprotein in the air spaces, increased protein content in bronchoalveolar lavage fluid, and altered surfactant activity in vitro. Consistent with surfactant dysfunction, hysteresis, maximal tidal volumes, and end expiratory volumes were decreased. Reduction of alveolar SP-B content causes surfactant dysfunction and respiratory failure, indicating that SP-B is required for postnatal lung function.

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Potential Role for ADAM15 in Pathological Neovascularization in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.23.16.5614-5624.2003 ◽

2003 ◽

Vol 23 (16) ◽

pp. 5614-5624 ◽

Cited By ~ 125

Author(s):

Keisuke Horiuchi ◽

Gisela Weskamp ◽

Lawrence Lum ◽

Hans-Peter Hammes ◽

Hui Cai ◽

...

Keyword(s):

Wild Type ◽

Developmental Defects ◽

Targeted Deletion ◽

Adult Mice ◽

Cell Matrix ◽

Mrna In Situ Hybridization ◽

Matrix Interactions ◽

Novel Target ◽

High Level ◽

Cell Matrix Interactions

ABSTRACT ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15−/− mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15−/− mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15−/− mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15−/− mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization.

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