Expression patterns of MLC1 protein in the central and peripheral nervous systems.
ABSTRACT Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a disorder characterized clinically by macrocephaly, deterioration of motor functions, epilepsy and mental decline. Recent studies have detected MLC1 mRNA and protein in astroglial processes. In addition, our group previously reported MLC1 expression in some neurons in the adult mouse brain. Here we performed an exhaustive study of the expression pattern of MLC1 in the developing mouse brain by means of optic and electron microscopy. In the central nervous system, MLC1 was detected mainly in axonal tracts early in development. In addition, MLC1 was also observed in the peripheral nervous system and in several sensory epithelia, as retina or saccula maculae. Post-embedding immunogold experiments indicated that MLC1 is localized in astrocyte-astrocyte junctions, but not in the perivascular membrane, indicating that MLC1 is not a component of the dystrophin-glycoprotein complex. In neurons, MLC1 is located at the plasma membrane and vesicular structures. Our data provide a mouse MLC1 expression map that could be useful to understand the phenotype of MLC patients, and suggested that MLC disease is caused by an astrocytic and a neuronal dysfunction.
- SourceAvailable from: Michiko Mandai[Show abstract] [Hide abstract]
ABSTRACT: Retinal Müller glia can serve as a source for regeneration of damaged retinal neurons in fish, birds and mammals. However, the proliferation rate of Müller glia has been reported to be low in the mammalian retina. To overcome this problem, growth factors and morphogens have been studied as potent promoters of Müller glial proliferation, but the molecular mechanisms that limit the proliferation of Müller glia in the mammalian retina remain unknown. In the present study, we found that the degree of damage-induced Müller glia proliferation varies across mouse strains. In mouse line 129×1/SvJ (129), there was a significantly larger proliferative response compared with that observed in C57BL/6 (B6) after photoreceptor cell death. Treatment with a Glycogen synthase kinase 3 (GSK3) inhibitor enhanced the proliferation of Müller glia in 129 but not in B6 mouse retinas. We therefore focused on the different gene expression patterns during retinal degeneration between B6 and 129. Expression levels of Cyclin D1 and Nestin correlated with the degree of Müller glial proliferation. A comparison of genome-wide gene expression between B6 and 129 showed that distinct sets of genes were upregulated in the retinas after damage, including immune response genes and chromatin remodeling factors.PLoS ONE 04/2014; 9(4):e94556. · 3.53 Impact Factor
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ABSTRACT: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by myelin vacuolization and caused by mutations in MLC1 or GLIALCAM. Patients with recessive mutations in either MLC1 or GLIALCAM show the same clinical phenotype. It has been shown that GLIALCAM is necessary for the correct targeting of MLC1 to the membrane at cell junctions, but its own localization was independent of MLC1 in vitro. However, recent studies in Mlc1(-/-) mice have shown that GlialCAM is mislocalized in glial cells. In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1(-/-) zebrafish. We have characterized mlc1(-/-) zebrafish both functionally and histologically and compared the phenotype with that of the Mlc1(-/-) mice. In mlc1(-/-) zebrafish, as in Mlc1(-/-) mice, Glialcam is mislocalized. Re-examination of a brain biopsy from an MLC patient indicates that GLIALCAM is also mislocalized in Bergmann glia in the cerebellum. In vitro, impaired localization of GlialCAM was observed in astrocyte cultures from Mlc1(-/-) mouse only in the presence of elevated potassium levels, which mimics neuronal activity. In summary, here we demonstrate an evolutionary conserved role for MLC1 in regulating glial surface levels of GLIALCAM, and this interrelationship explains why patients with mutations in either gene (MLC1 or GLIALCAM) share the same clinical phenotype.Human Molecular Genetics 05/2014; · 6.68 Impact Factor
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ABSTRACT: Key Clinical MessageMegalencephalic leukoencephalopathy (MLC) is a rare neurological disorder with an autosomal recessive pattern. Clinical diagnosis was based on macrocephaly, recurrent seizure, and magnetic resonance imaging (MRI). Here we report first finding of a novel homozygous single base deletion in the MLC1 gene in an affected Iranian child causing a premature stop codon (p.L150fs.160X).Clinical Case Reports. 11/2014;