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

Autor:	Arnold TD; Department of Pediatrics, University of California, San Francisco, San Francisco, CA arnoldt@peds.ucsf.edu., Lizama CO; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA., Cautivo KM; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA., Santander N; Department of Pediatrics, University of California, San Francisco, San Francisco, CA., Lin L; Department of Pediatrics, University of California, San Francisco, San Francisco, CA., Qiu H; Department of Pathology, University of California, San Francisco, San Francisco, CA.; Department of Neurology, University of California, San Francisco, San Francisco, CA., Huang EJ; Department of Pathology, University of California, San Francisco, San Francisco, CA.; Department of Neurology, University of California, San Francisco, San Francisco, CA., Liu C; Laboratory of Stem Cell and Neuro-Vascular Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD., Mukouyama YS; Laboratory of Stem Cell and Neuro-Vascular Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD., Reichardt LF; Department of Physiology and Neuroscience Program, University of California, San Francisco, San Francisco, CA., Zovein AC; Department of Pediatrics, University of California, San Francisco, San Francisco, CA.; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA., Sheppard D; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.; Department of Medicine, University of California, San Francisco, San Francisco, CA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2019 Apr 01; Vol. 216 (4), pp. 900-915. Date of Electronic Publication: 2019 Mar 07.
DOI:	10.1084/jem.20181290
Abstrakt:	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. (© 2019 Arnold et al.)
Databáze:	MEDLINE
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