Impaired SDF1/CXCR4 signaling in glial progenitors derived from SOD1(G93A) mice.
Mutations in the superoxide dismutase 1 (SOD1) gene are associated with familial amyotrophic lateral sclerosis (ALS), and the SOD1(G93A) transgenic mouse has been widely used as one animal model for studies of this neurodegenerative disorder. Recently, several reports have shown that abnormalities in neuronal development in other models of neurodegeneration occur much earlier than previously thought. To study the role of mutant SOD1 in glial progenitor biology, we immortalized glial restricted precursors (GRIPs) derived from mouse E11.5 neural tubes of wild-type and SOD1(G93A) mutant mice. Immunocytochemistry using cell lineage markers shows that these cell lines can be maintained as glial progenitors, because they continue to express A2B5, with very low levels of glial fibrillary acidic protein (astrocyte), betaIII-tubulin (neuron), and undetected GalC (oligodendrocyte) markers. RT-PCR and immunoblot analyses indicate that the chemokine receptor CXCR4 is reduced in SOD1(G93A) GRIPs. Subsequently, SOD1(G93A) GRIPs are unable to respond to SDF1alpha to activate ERK1/2 enzymes and the transcription factor CREB. This may be one pathway leading to a reduction in SOD1(G93A) cell migration. These data indicate that the abnormalities in SOD1(G93A) glial progenitor expression of CXCR4 and its mediated signaling and function occur during spinal cord development and highlight nonneuronal (glial) abnormalities in this ALS model.
Luo
Yongquan
Y
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA.
Xue
Haipeng
H
Pardo
Andrea C
AC
Mattson
Mark P
MP
Rao
Mahendra S
MS
Maragakis
Nicholas J
NJ
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology*; D013234:Stem Cells / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase