Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle.
OBJECTIVE
Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic disease characterized by infantile onset white matter edema and delayed onset neurological deterioration. Loss of MLC1 function causes MLC. MLC1 is involved in ion-water homeostasis, but its exact role is unknown. We generated Mlc1-null mice for further studies.


METHODS
We investigated which brain cell types express MLC1, compared developmental expression in mice and men, and studied the consequences of loss of MLC1 in Mlc1-null mice.


RESULTS
Like humans, mice expressed MLC1 only in astrocytes, especially those facing fluid-brain barriers. In mice, MLC1 expression increased until 3 weeks and then stabilized. In humans, MLC1 expression was highest in the first year, decreased, and stabilized from approximately 5 years. Mlc1-null mice had early onset megalencephaly and increased brain water content. From 3 weeks, abnormal astrocytes were present with swollen processes abutting fluid-brain barriers. From 3 months, widespread white matter vacuolization with intramyelinic edema developed. Mlc1-null astrocytes showed slowed regulatory volume decrease and reduced volume-regulated anion currents, which increased upon MLC1 re-expression. Mlc1-null astrocytes showed reduced expression of adhesion molecule GlialCAM and chloride channel ClC-2, but no substantial changes in other known MLC1-interacting proteins.


CONCLUSIONS
Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.
Department of Pediatrics/Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University.
Mohit
M
Dubey
Marianna
M
Bugiani
Margreet C
MC
Ridder
Nienke L
NL
Postma
Eelke
E
Brouwers
Emiel
E
Polder
J Gerbren
JG
Jacobs
Johannes C
JC
Baayen
Jan
J
Klooster
Maarten
M
Kamermans
Romy
R
Aardse
Christiaan P J
CP
de Kock
Marien P
MP
Dekker
Jan R T
JR
van Weering
Vivi M
VM
Heine
Truus E M
TE
Abbink
Gert C
GC
Scheper
Ilja
I
Boor
Johannes C
JC
Lodder
Huibert D
HD
Mansvelder
Marjo S
MS
van der Knaap
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003560:Cysts / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D004856:Postural Balance / Q000235:genetics; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D012678:Sensation Disorders / Q000235:genetics; D066127:White Matter / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
D008565:Membrane Proteins; C498927:Mlc1 protein, mouse; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human