Abstract

Growth arrest-specific protein 6 (gas6) activities are mediated through the Tyro3, Axl, and Mer family of receptor tyrosine kinases. Gas6 is expressed and secreted by a wide variety of cell types, including cells of the central nervous system (CNS). In this study, we tested the hypothesis that administration of recombinant human Gas6 (rhGas6) protein into the CNS improves recovery following cuprizone withdrawal. After a 4-week cuprizone diet, cuprizone was removed and PBS or rhGas6 (400 ng/ml, 4 µg/ml and 40 µg/ml) was delivered by osmotic mini-pump into the corpus callosum of C57Bl6 mice for 14 days. Nine of 11 (82%) PBS-treated mice had abundant lipid-associated debris in the corpus callosum by Oil-Red-O staining while only 4 of 19 (21%) mice treated with rhGas6 had low Oil-Red-O positive droplets. In rhGas6-treated mice, SMI32-positive axonal spheroids and APP-positive deposits were reduced in number relative to PBS-treated mice. Compared to PBS, rhGas6 enhanced remyelination as revealed by MBP immunostaining and electron microscopy. The rhGas6-treated mice had more oligodendrocytes expressing Olig1 in the cytoplasm, indicative of oligodendrocyte progenitor cell maturation. Relative to PBS-treated mice, rhGas6-treated mice had fewer activated microglia in the corpus callosum by Iba1 immunostaining. The data show that rhGas6 treatment resulted in more efficient repair following cuprizone-induced injury.

Highlights

  • Gas6, the product of growth arrest-specific gene 6 (Gas6), is upregulated during growth arrest [1,2,3], and is expressed and secreted by a wide variety of cell types including neurons [3,4]

  • These results demonstrated that all recombinant human Gas6 (rhGas6) doses had a beneficial effect on the clearance of cellular and myelin debris following cuprizone toxicity

  • We show that compared to mice receiving PBS, rhGas6 administration directly to the corpus callosum by osmotic mini-pump for 14 days enhanced the clearance of lipid-laden debris, remyelination and reduced axonal damage that resulted from 4 weeks of ingestion of cuprizone in powdered chow

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Summary

Introduction

The product of growth arrest-specific gene 6 (Gas6), is upregulated during growth arrest [1,2,3], and is expressed and secreted by a wide variety of cell types including neurons [3,4]. Gas is a vitamin K-dependent growth factor and is the ligand for the Tyro, Axl, and Mer (TAM) receptor tyrosine kinase family [5,6]. In a concentration-dependent manner, Gas induces signaling through TAM receptors and exerts its biological effects [7,8,9,10,11,12]. Gas binds phosphatidylserine and promotes phagocytosis of apoptotic cells [21]. Shed soluble forms of Axl and Mer bind Gas and can function as decoy receptors regulating Gas bioactivity [22,23]. In multiple sclerosis (MS) lesions, upregulation of soluble Axl and Mer negatively correlates with Gas expression, suggesting that the dysregulation of protective Gas receptor signaling may prolong lesion activity [24]

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