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Cited by 67Neuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanismsNeonatal and fetal brain pathology

Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction

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Arnold, Thomas D., Lizama, Carlos O., Cautivo, Kelly M., Santander, Nicolas, Lin, Lucia, Qiu, Haiyan, Huang, Eric J., Liu, Chang +4 more·2019·Journal of Experimental Medicine
DOI 10.1084/jem.20181290PMC PMC6446869
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Abstract

Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of αVβ8 from the central nervous system (Itgb8ΔCNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These “dysmature” microglia appear to result from reduced TGFβ signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGFβ signaling during adulthood, and directly cause a unique neurodevelopmental syndrome characterized by oligodendrocyte maturational arrest, interneuron loss, and spastic neuromotor dysfunction. Consistent with this, early (but not late) microglia depletion completely reverses this phenotype. Together, these data identify novel roles for αVβ8 and TGFβ signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.

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Authors
Arnold, T. D., Lizama, C. O., Cautivo, K. M., Santander, N., Lin, L., Qiu, H., Huang, E. J., Liu, C., Mukouyama, Y.-S., Reichardt, L. F., Zovein, A. C., & Sheppard, D.
Affiliations
  • University of California, San Francisco (US)
  • National Institutes of Health (US)
Corresponding author
Arnold, Thomas D.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2019-03-07
Volume
216
Issue
4
Pages
900-915
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20181290
PMC
PMC6446869
OpenAlex
W2922287622
Cited by
67
References
64
Citations by year
2026: 13 · 2025: 15 · 2024: 11 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 8 · 2019: 2
FWCI
2.31
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Child Health and Human Development (K12HD047349)
  • National Heart, Lung, and Blood Institute (R37 HL53949)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
Keywords
microglia, integrin αvβ8, ITGB8, TGF-beta signaling, neurodevelopmental disorders, oligodendrocyte maturation, interneuron loss, spasticity, neuromotor dysfunction, conditional gene deletion, perinatal brain development, microglia depletion
MeSH terms
Receptor, Transforming Growth Factor-beta Type II, Animals, Brain, Female, Interneurons, Locomotion, Male, Mice, Inbred C57BL, Oligodendroglia, Phenotype, Signal Transduction, Integrins, Microglia, Mice, Knockout, Mice, Transforming Growth Factor beta1, Neurodevelopmental Disorders

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