The brain‐specific protein MLC1 implicated in megalencephalic leukoencephalopathy with subcortical cysts is expressed in glial cells in the murine brain

Abstract

The human MLC1 gene (also known as KIAA0027 and WKL1) and its murine orthologue (Mlc1) encode a putative transmembrane protein expressed primarily in brain. Recessive mutations within human MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), whereas a missense mutation resulting in a methionine substitution within a transmembrane leucine string of MLC has been implicated in catatonic schizophrenia in a large pedigree. To gain insight into the function of the MLC protein and to elucidate the pathophysiology of these severe neurodegenerative disorders, information on the cellular and regional distribution of the murine Mlc1, as well as the developmental pattern of Mlc1 expression in brain, is required. Using in situ hybridization (ISH), Mlc1 mRNA was exclusively detected in glial cells of the adult murine brain, such as astrocytes, Bergmann glia, and ependymal cells. ISH, Northern blot analysis, and quantitative real-time polymerase chain reaction (PCR) demonstrated that Mlc1 mRNA is broadly distributed in the adult mouse brain, with highest concentrations of expression in the cerebellum and olfactory bulb. Furthermore, differential expression patterns during brain development were revealed. Overall brain Mlc1 mRNA concentrations exhibited a substantial increase in the perinatal period reaching adult concentrations at postnatal day 5. At the cellular level, highest Mlc1 expression was found during the pre- and perinatal period in multipotential neural precursor cells, especially in the subventricular zone of the lateral ventricle, whereas in adulthood highest Mlc1 mRNA concentrations were revealed in Bergmann glia cells. Because the temporal expression profile of Mlc1 indicates that, in contrast to developing and mature astrocytes, oligodendrocytes are devoid of Mlc1 expression, white matter tract abnormalities observed in these disorders may result from a primary astrocytic defect. Detailed information on Mlc1 expression in brain is likely to lead to a better understanding of Mlc1 involvement in the pathogenesis of both MLC and catatonic schizophrenia.

Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation

“…To selectively stimulate the glia, we generated two lines of mice (20); one in which the expression of tetracycline-controlled tTA is driven by megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1)-promoter, which has been proven to be astrocyte specific (21), and the other in which tetO is connected to the expression of C128S mutant of ChR2 (19) fused with enhanced yellow fluorescent protein (EYFP). By obtaining bigenic [Mlc1-tTA::tetOChR2(C128S)-EYFP] mice, strong EYFP expression was found in BGs in the cerebellum (Fig.…”

Alexander Disease-Associated Glial Fibrillary Acidic Protein Mutations in Mice Induce Rosenthal Fiber Formation and a White Matter Stress Response

“…In MLC, patients suffer from recessive mutations in the MLC1 gene, which encodes a putative membrane channel that localizes to the distal processes of astrocytes in the perivascular, subependymal, and subpial regions (Boor et al, 2005). MLC1 is also expressed in Bergmann glia and olfactory bulb astrocytes, but not in oligodendrocytes (Schmitt et al, 2003).…”

Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

“…4), as previously described for ClC-2 and GlialCAM 8,12 . However, unlike ClC-2 and GlialCAM, MLC1 is apparently not expressed in OLs 2,19,20 . As MLC1 was detected in neighbouring bona fide astrocytes (Fig.…”