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Updated: Jan 3, 2026
Müller Glia Cell Activation in a Laser-induced Retinal Degeneration and Regeneration Model in Zebrafish
Published on: October 27, 2017
Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that
Carla Pérez-Rius1, Mónica Folgueira2,3, Xabier Elorza-Vidal1
1Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Background:
Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare type of leukodystrophy characterized by astrocyte and myelin vacuolization, epilepsy and early-onset macrocephaly. MLC is caused by mutations in MLC1 or GLIALCAM, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in Mlc1-/- or Glialcam-/- mice and mlc1-/- zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions.
Methods:
We have generated and analysed glialcama-/- zebrafish. We also generated zebrafish glialcama-/- mlc1-/- and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses.
Results:
glialcama-/- shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of mlc1. Unlike mice, mlc1 protein expression and localization are unaltered in glialcama-/- zebrafish, possibly because there is an up-regulation of mlc1 mRNA. In line with these results, MLC1 overexpressed in Glialcam-/- mouse primary astrocytes is located at cell-cell junctions.
Conclusions:
This work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway.
Insights
Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is caused by mutations in MLC1 and GlialCAM proteins. Loss of GlialCAM function in zebrafish and mice leads to megalencephaly, suggesting a common pathway in MLC pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare leukodystrophy.
- It is characterized by astrocyte vacuolization, epilepsy, and macrocephaly.
- MLC arises from mutations in MLC1 or GLIALCAM, forming a complex in astrocytes.
Purpose of the Study:
- To investigate the functional relationship between MLC1 and GlialCAM in vivo.
- To elucidate the common pathogenic pathway in MLC.
Main Methods:
- Generated Glialcam knockout zebrafish and double knockout mice (Mlc1-/- Glialcam-/-).
- Performed magnetic resonance imaging, histological, and biochemical analyses.
Main Results:
- Glialcam deficiency caused megalencephaly and fluid accumulation in zebrafish and mice.
- The phenotype was not worsened by additional Mlc1 deletion.
- MLC1 expression and localization remained normal in Glialcam-/- zebrafish, potentially due to mRNA upregulation.
Conclusions:
- MLC1 and GlialCAM form a functional unit in astrocytes.
- Loss-of-function mutations in MLC1 and GLIALCAM contribute to leukodystrophy via a shared mechanism.
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