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Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages
Julia Meller, … , Bruce D. Trapp, Tatiana V. Byzova
Julia Meller, … , Bruce D. Trapp, Tatiana V. Byzova
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e93002. https://doi.org/10.1172/jci.insight.93002.
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Research Article Cell biology Neuroscience

Integrin-Kindlin3 requirements for microglial motility in vivo are distinct from those for macrophages

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Abstract

Microglia play a critical role in the development and homeostasis of the CNS. While mobilization of microglia is critical for a number of pathologies, understanding of the mechanisms of their migration in vivo is limited and often based on similarities to macrophages. Kindlin3 deficiency as well as Kindlin3 mutations of integrin-binding sites abolish both integrin inside-out and outside-in signaling in microglia, thereby resulting in severe deficiencies in cell adhesion, polarization, and migration in vitro, which are similar to the defects observed in macrophages. In contrast, while Kindlin3 mutations impaired macrophage mobilization in vivo, they had no effect either on the population of microglia in the CNS during development or on mobilization of microglia and subsequent microgliosis in a model of multiple sclerosis. At the same time, acute microglial response to laser-induced injury was impaired by the lack of Kindlin3-integrin interactions. Based on 2-photon imaging of microglia in the brain, Kindlin3 is required for elongation of microglial processes toward the injury site and formation of phagosomes in response to brain injury. Thus, while Kindlin3 deficiency in human subjects is not expected to diminish the presence of microglia within CNS, it might delay the recovery process after injury, thereby exacerbating its complications.

Authors

Julia Meller, Zhihong Chen, Tejasvi Dudiki, Rebecca M. Cull, Rakhilya Murtazina, Saswat K. Bal, Elzbieta Pluskota, Samantha Stefl, Edward F. Plow, Bruce D. Trapp, Tatiana V. Byzova

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Figure 1

Kindlin3 is expressed in microglia in vitro and in vivo.

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Kindlin3 is expressed in microglia in vitro and in vivo.
(A) Brain tissu...
(A) Brain tissue from P9 Cx3cr1GFP/+ mice was stained for Kindlin3. Representative confocal image from the cortical region showing expression of Kindlin3 (red), GFP (green), and overlay (right), with nuclei shown in blue. Scale bar: 10 μm. (B) Projection of z-stack images showing Kindlin3 in whole-mount retinas from P9 Cx3cr1GFP/+ mice (Kindlin3, red; GFP, green; isolectin, blue). Scale bar: 100 μm. (C) 3D reconstitution of an image stack from P7 whole-mount retinas showing coexpression of CD11b (red) and Kindlin3 (green) within the same cells. Blood vessels are in blue (isolectin). Scale bar: 100 μm. (D) 3D reconstitution of a brain slice from the cortical region (left)showing lack of Kindlin3 expression (green) in GFAP-positive cells (red). Staining of cultured astrocytes and microglial cells (right) showing lack of Kindlin3 expression (green) in astrocytes (actin-rich cells predominantly stained with phalloidin, red). Nuclei are shown in blue. Scale bar: 10 μm. (E) P7 whole-mount retinas stained for Kindlin3 (green) and blood vessels (isolectin, red). Scale bar: 100 μm.

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