LFB staining demonstrates a reduction in the extent of remyelination in the absence of Gas6.

<p><b>A–F</b> Wild-type and Gas6 KO mice were subjected to cuprizone challenge for 5 weeks followed by recovery in the absence of cuprizone for 0, 2 or 4 weeks. <b>A</b>. The corpus callosum was divided into three segments for image analysis: rostral (R), Middle (M) and Caudal (C) <b>G–I</b> Myelin density was assessed using image analysis as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017727#s2" target="_blank">Materials and Methods</a>. <b>G</b>. A significant reduction in myelination was observed in the rostral segment of the corpus callosum (p = 0.039) and a strong trend towards reduction was observed in the middle segment (p = 0.052) (<b>H</b>). Scale bar = 1 mm.</p

EM analysis demonstrates that, following 10 weeks of recovery, Gas6 KO mice remyelinate to the same extent as Gas6 WT mice.

<p><b>A–L</b> Wild-type and Gas6 KO mice were subjected to cuprizone challenge for 5 weeks followed by recovery in the absence of cuprizone for 0 or 10 weeks. The number of myelinated axons/mm² was quantified in the rostral, middle and caudal segments of the corpus callosum (<b>M–O</b>). No significant differences were observed between Gas6^−/− or Gas6^+/+ mice at any time point or in segment (p>0.05). Scale bar = 2 µm.</p

EM analysis demonstrates a reduction in the number of myelinated axons during the course of remyelination in the absence of Gas6.

<p><b>A–F</b> Wild-type and Gas6 KO mice were subjected to cuprizone challenge for 5 weeks followed by recovery in the absence of cuprizone for 0, 2 or 4 weeks. The number of myelinated axons per mm² was quantified and shown in <b>G–I</b>. A significant reduction in myelination was observed in the caudal (<b>I</b>) segments of the corpus callosum in Gas6^−/− mice compared with Gas6^+/+ mice (p = 0.032). Scale bar = 2 µm.</p

Axon Diameter and <i>g</i>-ratios in Gas6^+/+ and Gas6^−/− mice during long-term remyelination.

<p>*p<0.05.</p

The number of IBA1 positive microglia is minimally altered by the absence of Gas6 during remyelination.

<p>Wild-type and Gas6 KO mice were subjected to cuprizone challenge for 5 weeks followed by recovery in the absence of cuprizone for 0, 2, 4 or 10 weeks. <b>A</b>. Representative images of the middle segment of the corpus callosum, showing cells positive for IBA1. <b>B–D</b> The number of IBA1 positive cells/mm2 was quantified. A significant increase in the number of IBA1-positive microglia was observed in Gas6^−/− mice compared with Gas6^+/+ mice following 10 weeks of remyelination (p = 0.031). Scale bar = 20 µm.</p

Axon Diameter and <i>g</i>-ratios in Gas6^+/+ and Gas6^−/− mice during remyelination.

<p>*p<0.05.</p

SNPs within <i>MERTK</i> define both risk and protective haplotypes associated with MS susceptibility.

<p>28 SNPs within the <i>MERTK</i> gene form a single block of very high LD (D'>0.99, LOD≥2). The five most frequent haplotypes (population frequency >1%) are shown in this schematic, along with the <i>p</i>-value of association of each haplotype with MS susceptibility as determined using a Chi-square test. Arrowhead indicates the haplotype-tagging allele of rs13414207 in haplotype 5. The alleles presented for rs17174870 are inferred from data obtained from sequencing the opposite strand but are presented as CT to maintain consistency with the remainder of the study.</p

Gene model association of rs13414207 with Multiple Sclerosis.

<p>Gene model association of rs13414207 with Multiple Sclerosis.</p

Top 10 SNPs within <i>MERTK</i> associated with Multiple Sclerosis susceptibility.

<p>Top 10 SNPs within <i>MERTK</i> associated with Multiple Sclerosis susceptibility.</p

The haplotype structure of variants identified in <i>MERTK</i>.

<p>The 52 variants in <i>MERTK</i> genotyped for association with MS susceptibility fall into 4 separate blocks. Haplotype blocks are connected with thick lines if connections are observed in >10% samples and thin lines if connections are observed in >1% samples. A schematic of the <i>MERTK</i> gene is shown underneath indicating the relationship of the blocks to the physical structure of <i>MERTK</i>. The haplotypes coloured in red are significantly associated with MS susceptibility (p<0.05) and the haplotype coloured in blue is associated with protection (p<0.05). The <i>p</i>-value of association was determined using a Chi-square test. #This variant represents a tri-nucleotide in-del (T/- = TGG; -)</p