Dap12 expression in activated microglia from retinoschisin-deficient retina and its PU.1-dependent promoter regulation
Abstract
Several alterations in the expression of immune-related transcripts were identified recently in the degenerating retina of the retinoschisin knockout (Rs1h(-/Y)) mouse, including the strong expression of the adaptor protein Dap12. As Dap12 is found in leukocytes, we hypothesized that its disease-related expression may be confined to activated retinal microglia cells. To test this hypothesis, we established a procedure for isolation and culture of retinal microglia cells and performed genome-wide expression profiling from Rs1h(-/Y) and control microglia. While retaining their activated state in culture, ex vivo microglia expressed high levels of Dap12 and the transcription factor PU.1. The activation-dependent induction of Dap12 was also confirmed in the microglia cell line BV-2 following in vitro stimulation. To examine the transcriptional regulation of Dap12 further, macrophage cell lines were transfected with several Dap12 reporter constructs. Promoter deletion assays and site-directed mutagenesis experiments demonstrated an essential role of evolutionarily conserved PU.1 consensus sites in the proximal -104/+118 Dap12 promoter. In vitro and in vivo binding of PU.1 to this promoter region was demonstrated using EMSA and chromatin immunoprecipitation. Knockdown of PU.1 by RNA interference caused a significant reduction of endogenous Dap12 expression and re-expression, and activation of PU.1 in PU.1(-/-) progenitor cells induced Dap12 transcription. Taken together, our result…
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PU.1 can bind to the Tyrobp gene promoter to activate Tyrobp expression.
“Interestingly, it was reported that PU.1 can bind to the Tyrobp gene promoter to activate Tyrobp expression40.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [40]
In our studies, the expression of Tyrobp was not altered in the same direction as reported.
“However, in our studies, the expression of Tyrobp was not altered in the same direction as reported40.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [40]
PU.1 induces the transcription of several surface receptors, such as ITGAM, VCAM1, TREM2, and TYROBP, thereby enhancing microglial phagocytic capacity for Aβ clearance.
“As shown in Figure 1, previous studies showed that PU.1 induces the transcription of several surface receptors, such as Integrin subunit alpha M (ITGAM, also known as CD11b), vascular cell adhesion molecule 1 (VCAM1, also known as CD106), TREM2, and TYROBP [32, 55], thereby enhancing microglial phagocytic capacity for Aβ clearance [56, 57].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [55]
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“genitor cell line with retroviral re-expression of the OHTinducible PU.1-ER fusion protein (PUER cells) [ 18 ].”
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Microglia in the healthy and degenerating retina: Insights from novel mouse models
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Self-citationThe transcription factor PU.1 is critical for viability and function of human brain microglia
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Kim, B., Dabin, L. C., Tate, M. D., Karahan, H., Sharify, A. D., Acri, D. J., Al-Amin, M. M., Philtjens, S., Smith, D. C., Wijeratne, H. R. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48484-x · Cited by 28 · see citing works
Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease
Kim, B., Wang, S. S., Kim, J. R., & Kim, J. (2026) · BioEssays · doi:10.1002/bies.70186
“…that PU.1 induces the transcription of several surface receptors, such as Integrin subunit alpha M (ITGAM, also known as CD11b), vascular cell adhesion molecule 1 (VCAM1, also known as CD106), TREM2, and TYROBP [32, 55], thereby enhancing microglial phagocytic capacity for A β clearance [56, 57].”
- Authors
- Weigelt, K., Ernst, W., Walczak, Y., Ebert, S., Loenhardt, T., Klug, M., Rehli, M., Weber, B. H. F., & Langmann, T.
- Affiliations
- University of Regensburg (DE)
- University Hospital Regensburg (DE)
- Corresponding author
- Langmann, Thomas
- Venue
- Journal of Leukocyte Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-07
- Volume
- 82
- Issue
- 6
- Pages
- 1564-1574
- ISSN
- 0741-5400 (ISSN-L)
- 1938-3673
- OpenAlex
- W2153596758
- Cited by
- 38
- References
- 7
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 3 · 2019: 1 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Leukocyte Biology (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Re1310/7, La1203/4-1)
- “Microglia activation in retinal degeneration”
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- DAP12, retinoschisin, retinal degeneration, retinal microglia, microglial activation, PU.1, transcriptional regulation, promoter regulation
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Binding Sites, Cell Separation, Eye Proteins, Gene Expression Regulation, HeLa Cells, Humans, Mice, Inbred C57BL, Molecular Sequence Data, Organ Specificity, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Retina, Stem Cells, Trans-Activators, Cell Adhesion Molecules, Conserved Sequence, Microglia, Evolution, Molecular, Gene Expression Profiling, Myeloid Cells, Adaptor Proteins, Signal Transducing, Mice
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