Absence of TGFβ signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.

Related collections

Most cited references 52

Record: found
Abstract: found
Article: not found

The Microglial Sensome Revealed by Direct RNA Sequencing

Suzanne E Hickman, Nathan D. Kingery, Toshiro K Ohsumi … (2013)

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.

0 comments Cited 677 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures.

Christopher Bohlen, F Bennett, Andrew Tucker … (2017)

Microglia, the resident macrophages of the CNS, engage in various CNS-specific functions that are critical for development and health. To better study microglia and the properties that distinguish them from other tissue macrophage populations, we have optimized serum-free culture conditions to permit robust survival of highly ramified adult microglia under defined-medium conditions. We find that astrocyte-derived factors prevent microglial death ex vivo and that this activity results from three primary components, CSF-1/IL-34, TGF-β2, and cholesterol. Using microglial cultures that have never been exposed to serum, we demonstrate a dramatic and lasting change in phagocytic capacity after serum exposure. Finally, we find that mature microglia rapidly lose signature gene expression after isolation, and that this loss can be reversed by engrafting cells back into an intact CNS environment. These data indicate that the specialized gene expression profile of mature microglia requires continuous instructive signaling from the intact CNS.

0 comments Cited 293 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes.

Mary Mattapallil, Eric F Wawrousek, Chi-Chao Chan … (2012)

We noted an unexpected inheritance pattern of lesions in several strains of gene-manipulated mice with ocular phenotypes. The lesions, which appeared at various stages of backcross to C57BL/6, bore resemblance to the rd8 retinal degeneration phenotype. We set out to examine the prevalence of this mutation in induced mutant mouse lines, vendor C57BL/6 mice and in widely used embryonic stem cells. Ocular lesions were evaluated by fundus examination and histopathology. Detection of the rd8 mutation at the genetic level was performed by PCR with appropriate primers. Data were confirmed by DNA sequencing in selected cases. Analysis of several induced mutant mouse lines with ocular disease phenotypes revealed that the disease was associated 100% with the presence of the rd8 mutation in the Crb1 gene rather than with the gene of interest. DNA analysis of C57BL/6 mice from common commercial vendors demonstrated the presence of the rd8 mutation in homozygous form in all C57BL/6N substrains, but not in the C57BL/6J substrain. A series of commercially available embryonic stem cells of C57BL/6N origin and C57BL/6N mouse lines used to generate ES cells also contained the rd8 mutation. Affected mice displayed ocular lesions typical of rd8, which were detectable by funduscopy and histopathology as early as 6 weeks of age. These findings identify the presence of the rd8 mutation in the C57BL/6N mouse substrain used widely to produce transgenic and knockout mice. The results have grave implications for the vision research community who develop mouse lines to study eye disease, as presence of rd8 can produce significant disease phenotypes unrelated to the gene or genes of interest. It is suggested that researchers screen for rd8 if their mouse lines were generated on the C57BL/6N background, bear resemblance to the rd8 phenotype, or are of indeterminate origin.

0 comments Cited 291 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Wenxin Ma:

ORCID: http://orcid.org/0000-0001-8396-6625

Lian Zhao:

ORCID: http://orcid.org/0000-0002-0120-1969

Rafael Villasmil

Maria M Campos

Juan Amaral

Wai T Wong:

ORCID: http://orcid.org/0000-0003-0681-4016

Constance L Cepko: Role: Reviewing Editor

Gary L Westbrook: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 22 January 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e42049

Affiliations

[1 ]deptUnit on Neuron-Glia Interactions in Retinal Disease National Eye Institute, National Institutes of Health BethesdaUnited States

[2 ]deptFlow Cytometry Core Facility National Eye Institute, National Institutes of Health BethesdaUnited States

[3 ]deptSection on Histopathology National Eye Institute, National Institutes of Health BethesdaUnited States

[4 ]deptUnit on Ocular Stem Cell and Translational Research National Eye Institute, National Institutes of Health BethesdaUnited States

Harvard Medical School United States

Vollum Institute United States

Harvard Medical School United States

Author information

Wenxin Ma http://orcid.org/0000-0001-8396-6625

Lian Zhao http://orcid.org/0000-0002-0120-1969

Wai T Wong http://orcid.org/0000-0003-0681-4016

Article

Publisher ID: 42049

DOI: 10.7554/eLife.42049

PMC ID: 6342522

PubMed ID: 30666961

SO-VID: 7798ed1a-a74f-47a6-a00d-65a115ac30c1

License:

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 15 September 2018

Date accepted : 02 January 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000053, National Eye Institute;

Award ID: Intramural Research Program

Award Recipient : Wai T Wong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement TGFβ signaling to retinal microglia is central to the regulation of neuroinflammatory responses relevant to age-related macular degeneration (AMD), a leading cause of blindness in the developed world.

ScienceOpen disciplines: Life sciences

Keywords: microglia,tgf,retina,age-related macular degeneration,neovascularization,neurodegeneration,mouse

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: microglia, tgf, retina, age-related macular degeneration, neovascularization, neurodegeneration, mouse

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Cited by 50

See all cited by

Most referenced authors 1,216

See all reference authors

Absence of TGFβ signaling in retinal microglia induces retinal degeneration and exacerbates choroidal neovascularization

Read this article at

Abstract

Related collections

Neuronal Signaling

Most cited references 52

The Microglial Sensome Revealed by Direct RNA Sequencing

Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures.

The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes.

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 663

Cited by 50

Most referenced authors 1,216