title: Megalencephalic leukoencephalopathy with subcortical cysts protein-1 regulates epidermal growth factor receptor signaling in astrocytes.
abstract: Mutations in the MLC1 gene, which encodes a protein expressed in brain astrocytes, are the leading cause of MLC, a rare leukodystrophy characterized by macrocephaly, brain edema, subcortical cysts, myelin and astrocyte vacuolation. Although recent studies indicate that MLC1 protein is implicated in the regulation of cell volume changes, the exact role of MLC1 in brain physiology and in the pathogenesis of MLC disease remains to be clarified. In preliminary experiments, we observed that MLC1 was poorly expressed in highly proliferating astrocytoma cells when compared with primary astrocytes, and that modulation of MLC1 expression influenced astrocyte growth. Because volume changes are key events in cell proliferation and during brain development MLC1 expression is inversely correlated to astrocyte progenitor proliferation levels, we investigated the possible role for MLC1 in the control of astrocyte proliferation. We found that overexpression of wild type but not mutant MLC1 in human astrocytoma cells hampered cell growth by favoring epidermal growth factor receptor (EGFR) degradation and by inhibiting EGF-induced Ca(+) entry, ERK1/2 and PLCγ1 activation, and calcium-activated KCa3.1 potassium channel function, all molecular pathways involved in astrocyte proliferation stimulation. Interestingly, MLC1 did not influence AKT, an EGFR-stimulated kinase involved in cell survival. Moreover, EGFR expression was higher in macrophages derived from MLC patients than from healthy individuals. Since reactive astrocytes proliferate and re-express EGFR in response to different pathological stimuli, the present findings provide new information on MLC pathogenesis and unravel an important role for MLC1 in other brain pathological conditions where astrocyte activation occurs.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Lanciotti
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: Brignone
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Visentin
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Nuccio
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, Perugia 06123, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Catacuzzeno
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Mallozzi
authors.affiliation: Research Center, Confocal Microscopy Core Facility, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, Rome 00146, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrini
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, Perugia 06123, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Caramia
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Veroni
authors.affiliation: Research Center, Confocal Microscopy Core Facility, Bambino Gesù Children's Hospital, IRCCS, Viale San Paolo 15, Rome 00146, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: Minnone
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Bernardo
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, via Elce di Sotto 8, Perugia 06123, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Franciolini
authors.affiliation: Faculty of Medicine, Section of Physiology & Biochemistry, Department of Experimental Medicine, University of Perugia, P.le Gambuli 1-06132 San Sisto, Perugia 06126, Italy, Department of Physiology & Biochemistry, Faculty of Medicine & Surgery, University of Malta, Msida, Malta and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesu' Children's Research Hospital, V.le S. Paolo, 15, Rome 00146, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Tamara Corinna
authors.initials: TC
authors.lastname: Petrucci
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy, elena.ambrosini@iss.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrosini
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003560:Cysts / Q000235:genetics / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D051381:Rats; D015398:Signal Transduction
chemical_list: C000612701:MLC1 membrane protein, rat; C425069:MLC1 protein, human; D008565:Membrane Proteins; D066246:ErbB Receptors