Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure

Alex K. Ray, Juwen C. Dubois, Ross C. Gruber, Hillary M. Guzik, Maria E. Gulinello, Geoffrey Perumal, Cedric Raine, Lauren Kozakiewicz, Julie Williamson, Bridget Shafit-Zagardo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and ProS1, are important for innate immune responses and central nervous system (CNS) homeostasis. While only Gas6 directly activates Axl, ProS1 activation of Tyro3/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6-/-Axl-/- double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that naïve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3-weeks recovery from a 6-week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia/macrophages between the groups of mice. However, at 6-weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6-Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6-Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1/Tyro3/MerTK signaling.

Original languageEnglish (US)
JournalGLIA
DOIs
StateAccepted/In press - 2017

Fingerprint

Cuprizone
Knockout Mice
Axons
Cytokines
Central Nervous System
Multivesicular Bodies
Corpus Callosum
Oligodendroglia
Receptor Protein-Tyrosine Kinases
Microglia
Demyelinating Diseases
Myelin Sheath
Transmission Electron Microscopy
Innate Immunity
Astrocytes
Young Adult
Homeostasis
Macrophages
Staining and Labeling
Diet

Keywords

  • Axonal damage
  • Demyelination
  • Motor deficits
  • Neuroinflammation
  • TAM signaling

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure. / Ray, Alex K.; Dubois, Juwen C.; Gruber, Ross C.; Guzik, Hillary M.; Gulinello, Maria E.; Perumal, Geoffrey; Raine, Cedric; Kozakiewicz, Lauren; Williamson, Julie; Shafit-Zagardo, Bridget.

In: GLIA, 2017.

Research output: Contribution to journalArticle

Ray, Alex K. ; Dubois, Juwen C. ; Gruber, Ross C. ; Guzik, Hillary M. ; Gulinello, Maria E. ; Perumal, Geoffrey ; Raine, Cedric ; Kozakiewicz, Lauren ; Williamson, Julie ; Shafit-Zagardo, Bridget. / Loss of Gas6 and Axl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure. In: GLIA. 2017.
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AU - Ray, Alex K.

AU - Dubois, Juwen C.

AU - Gruber, Ross C.

AU - Guzik, Hillary M.

AU - Gulinello, Maria E.

AU - Perumal, Geoffrey

AU - Raine, Cedric

AU - Kozakiewicz, Lauren

AU - Williamson, Julie

AU - Shafit-Zagardo, Bridget

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AB - The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and ProS1, are important for innate immune responses and central nervous system (CNS) homeostasis. While only Gas6 directly activates Axl, ProS1 activation of Tyro3/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6-/-Axl-/- double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that naïve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3-weeks recovery from a 6-week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia/macrophages between the groups of mice. However, at 6-weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6-Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6-Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1/Tyro3/MerTK signaling.

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