Publication Date:
2016-04-07
Description:
Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fourgeaud, Lawrence -- Traves, Paqui G -- Tufail, Yusuf -- Leal-Bailey, Humberto -- Lew, Erin D -- Burrola, Patrick G -- Callaway, Perri -- Zagorska, Anna -- Rothlin, Carla V -- Nimmerjahn, Axel -- Lemke, Greg -- DP2 NS083038/DP/NCCDPHP CDC HHS/ -- DP2 NS083038/NS/NINDS NIH HHS/ -- P30CA014195/CA/NCI NIH HHS/ -- R01 AI089824/AI/NIAID NIH HHS/ -- R01 AI101400/AI/NIAID NIH HHS/ -- R01 NS085296/NS/NINDS NIH HHS/ -- R01 NS085938/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 14;532(7598):240-4. doi: 10.1038/nature17630. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain. ; Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Joint Master in Neuroscience Program, University of Strasbourg, Strasbourg 67081, France. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049947" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis
;
Brain/blood supply/cytology/*metabolism/pathology
;
Brain Injuries/metabolism/pathology
;
Disease Models, Animal
;
Female
;
Inflammation/metabolism
;
Intercellular Signaling Peptides and Proteins/metabolism
;
Ligands
;
Male
;
Mice
;
Microglia/*physiology
;
Neurogenesis
;
Parkinson Disease/metabolism
;
Phagocytosis
;
Protein S/metabolism
;
Proto-Oncogene Proteins/deficiency/*metabolism
;
Receptor Protein-Tyrosine Kinases/deficiency/*metabolism
;
Signal Transduction
;
Stem Cell Niche
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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