Expression patterns of MLC1 protein in the central and peripheral nervous systems

Teijido, Óscar; Casaroli‐Marano, Ricardo P.; Kharkovets, Tatjana; Aguado, Fernando; Zorzano, António; Palacı́n, Manuel; Soriano, Eduardo; Martı́nez, Albert; Estévez, Raúl

doi:10.1016/j.nbd.2007.01.016

Cited by 48 publications

(53 citation statements)

References 29 publications

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“…Astrocytes express different types of ion channels and gap junctional coupling within different brain regions, accounting for different electrophysiological properties 38. MLC1 expression in mice is highest in the cerebellum,39 but regional expression of GlialCAM is unexplored.…”

Section: Discussionmentioning

confidence: 99%

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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ObjectiveMegalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.MethodsWe investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men.Results Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.Interpretation Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.

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Section: Discussionmentioning

confidence: 99%

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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“…MLC1 is mostly expressed in astrocyte–astrocyte junctions of blood– and CSF− brain barriers, Bergmann glia and main axonal tracts [5], [8], [9]. The GlialCAM is regarded as an MLC1 beta-subunit and affects MLC1 directly in astrocyte–astrocyte junctions.…”

Section: Discussionmentioning

confidence: 99%

“…MLC1 is homologous with carrier proteins and is confined to the plasma membrane, which indicates that it may regulate substance translocation across the cell membrane [3], [7]. Besides, it has not yet been determined whether MLC1 is localized in membrane contact regions between endothelial cells and glial cells or between different kinds of glial cells [8]–[10].…”

Section: Introductionmentioning

confidence: 99%

Functional Studies of MLC1 Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts

et al. 2012

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC, MIM# 604004) is an autosomal recessive inherited disease mostly resulting from MLC1 mutations. In this study, we finished the functional analysis of MLC1 mutations identified recently in Chinese patients, including five newly described missense mutations (R22Q, A32V, G73E, A275T, Y278H), one known nonsense mutation (Y198X), and two known missense mutations (S69L, T118M). We found MLC1wt was localized to the cell periphery, whereas mutant R22Q, A32V, G73E, S69L and T118M were trapped in the lumen of endoplasmic reticulum (ER) when we transfected the wild-type and mutant MLC1 in U373MG cells. Compared to wild type, the mutant G73E, T118M, Y198X and A275T transcript decreased and all mutants except R22Q had lower protein expression in transfected U373MG cells. Therefore, we propose that all these eight MLC1 mutations had functional effect either on their protein/mRNA expression, or on their intracellular protein localization, or both.

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“…However, it has been published that MLC1 protein is expressed in astrocyte membranes and we had verified the gene expression. 10,17 Thus, it can be assumed that there is a translation process. Furthermore, we tested several promoter constructs, containing different parts of the 5'UTR and hence, sequences with different ATGs.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] In mice, MLC1 expression has also been detected in neurons. 10 Immunostaining and electron microscopy demonstrated the localization of MLC1 in perivascular astrocytic end-feet and astrocyte-astrocyte contact regions. MLC1 is concentrated at brain barriers like pia mater and ependyma.…”

Section: Introductionmentioning

confidence: 98%

Unusual 5'-regulatory structure and regulation of the murine Mlc1 gene: Lack of promoter-specific functional elements

Henseler

Turner

Eckhardt

et al. 2011

J Nucleic Acids Invest

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The MLC1 gene is involved in an autosomal recessive neurological disorder, megalencephalic leucoencephalopathy with subcortical cysts (MLC), which is characterized by macrocephaly during the first year of life and swollen white matter (leucoencephaly). Variants of MLC1 have also been associated with psychiatric disorders such as schizophrenia, major depression and bipolar disorder. Currently, little is known about the encoded protein (MLC1). Judging from its similarity to other known proteins, it may serve as a trans-membrane transporter. However, the function of the encoded protein and its gene regulation has not been investigated successfully so far. We investigated the 5’ region of the murine Mlc1 with respect to regulatory elements for gene expression. A promoter search and an in silico analysis were conducted. Luciferase reporter gene constructs with potential promoter regions were created to study promoter activity in vitro. We found two alternative first exons for the murine Mlc1 but were not able to detect any promoter activity for the investigated reporter gene constructs in different cell lines, thus pointing to the presence of essential cis-acting elements far outside of the region. In silico analysis indicated an uncommon promoter structure for Mlc1, with CCAAT-boxes representing the only noticeable elements.

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Expression patterns of MLC1 protein in the central and peripheral nervous systems

Cited by 48 publications

References 29 publications

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Functional Studies of MLC1 Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts

Unusual 5'-regulatory structure and regulation of the murine Mlc1 gene: Lack of promoter-specific functional elements

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