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Cited by 87Neuroinflammation and Neurodegeneration MechanismsTGF-β signaling in diseasesGenomics and Chromatin Dynamics

SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity

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Fixsen, Bethany R., Han, Claudia Z., Zhou, Yi, Spann, Nathanael J., Saisan, Payam, Shen, Zeyang, Balak, Christopher, Sakai, Mashito +14 more·2023·Nature Immunology
DOI 10.1038/s41590-023-01528-8PMC PMC10307637
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Abstract

Spalt-like transcription factor 1 (SALL1) is a critical regulator of organogenesis and microglia identity. Here we demonstrate that disruption of a conserved microglia-specific super-enhancer interacting with the Sall1 promoter results in complete and specific loss of Sall1 expression in microglia. By determining the genomic binding sites of SALL1 and leveraging Sall1 enhancer knockout mice, we provide evidence for functional interactions between SALL1 and SMAD4 required for microglia-specific gene expression. SMAD4 binds directly to the Sall1 super-enhancer and is required for Sall1 expression, consistent with an evolutionarily conserved requirement of the TGFβ and SMAD homologs Dpp and Mad for cell-specific expression of Spalt in the Drosophila wing. Unexpectedly, SALL1 in turn promotes binding and function of SMAD4 at microglia-specific enhancers while simultaneously suppressing binding of SMAD4 to enhancers of genes that become inappropriately activated in enhancer knockout microglia, thereby enforcing microglia-specific functions of the TGFβ–SMAD signaling axis.

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  • Monocyte-derived brain macrophages have been reported earlier, but these studies were largely focused on conditions of experimental challenge.

    “Monocyte-derived brain M F have been reported earlier, but these studies were largely focused on conditions of experimental challenge 20-25,59 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [20]

  • Monocyte and monocyte-derived macrophage contributions to brain pathologies are well documented in various animal models and human disorders.

    “Involvement of these cells has been shown in the development, progression and resolution of experimental autoimmune encephalitis (EAE) 20-22 , stroke 23,24 , Alzheimer's disease 25,26 and viral encephalitis 27 .”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [20]

    The Main section discusses disease roles for resident microglia, not monocytes or monocyte-derived macrophages. The Results section mentions macrophages engrafting after microglial depletion, but does not link them to the development, progression, or resolution of EAE, stroke, Alzheimer’s disease, or viral encephalitis. Searches for those conditions and for monocyte-derived macrophages found no passage establishing the attributed claim. (LLM, conf=0.75)

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Authors
Fixsen, B. R., Han, C. Z., Zhou, Y., Spann, N. J., Saisan, P., Shen, Z., Balak, C., Sakai, M., Cobo, I., Holtman, I. R., Warden, A. S., Ramirez, G., Collier, J. G., Pasillas, M. P., Yu, M., Hu, R., Li, B., Belhocine, S., Gosselin, D., Coufal, N. G., Ren, B., & Glass, C. K.
Affiliations
  • University of California San Diego (US)
  • University Medical Center Groningen (NL)
  • Université Laval (CA)
Corresponding author
Glass, Christopher K.
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2023-06-15
Volume
24
Issue
7
Pages
1188-1199
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-023-01528-8
PMC
PMC10307637
OpenAlex
W4380871083
Cited by
87
References
20
Citations by year
2026: 39 · 2025: 30 · 2024: 18
FWCI
8.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NS096170, NS109200, NS124637)
  • Cure Alzheimer’s Fund (306938)
  • JPB Foundation (KR29574)
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (1F30AG062159)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (K99MH129983)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
SALL1, SMAD4, super-enhancers, TGF-beta signaling, cell type-specific gene expression, transcriptional regulation, Drosophila wing development, enhancer binding sites
MeSH terms
Animals, Binding Sites, DNA, Promoter Regions, Genetic, Transcription Factors, Transforming Growth Factor beta, Microglia, Mice, Knockout, Mice

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