TAM receptors regulate multiple features of microglial physiology

Nature. 2016 Apr 14;532(7598):240-244. doi: 10.1038/nature17630. Epub 2016 Apr 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Brain / blood supply
  • Brain / cytology
  • Brain / metabolism*
  • Brain / pathology
  • Brain Injuries / metabolism
  • Brain Injuries / 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
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / deficiency
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Stem Cell Niche
  • Up-Regulation
  • c-Mer Tyrosine Kinase

Substances

  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Protein S
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase