Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons
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Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons. / Michelson, Piret; Hartwig, Christine; Schachner, Melitta; Gal, Andreas; Veske, Andres; Finckh, Ulrich; Petersen, Christine.
In: HUM MUTAT, Vol. 20, No. 6, 12.2002, p. 481-2.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons
AU - Michelson, Piret
AU - Hartwig, Christine
AU - Schachner, Melitta
AU - Gal, Andreas
AU - Veske, Andres
AU - Finckh, Ulrich
AU - Petersen, Christine
N1 - Copyright 2002 Wiley-Liss, Inc.
PY - 2002/12
Y1 - 2002/12
N2 - Mutations in L1CAM, the gene encoding the transmembrane multifunctional neuronal adhesion molecule L1, are associated with neurodevelopmental disorders including X-linked hydrocephalus and mental retardation. Some amino acid substitutions in various extracellular domains of L1 are known to affect posttranslational processing of the protein or its homophilic and heterophilic interactions. It is largely unknown, however, how these mutations result in neurodevelopmental disturbances and whether the effects of mutations on neurodevelopment can be modeled in vitro. We stably expressed full-length human wild type L1 and the known pathogenic missense mutations I179S, R184W, Y194C, and C264Y in NIH-3T3 cells. L1 protein synthesis, glycosylation pattern, and subcellular localization were analyzed. Neurite outgrowth of primary murine cerebellar neurons was measured after 23 hrs of co-cultivation using transfected NIH-3T3 cells as substrate. Like wild type L1, L1 protein with I179S or Y194C mutations was localized on the surface of the transfected substrate cells, but this was not the case with R184W or C264Y mutations. All four mutations were associated with reduced stimulation of neurite outgrowth. Measurement of neurite outgrowth on transfected substrate cells may be a suitable model for studying neurodevelopmental disturbances.
AB - Mutations in L1CAM, the gene encoding the transmembrane multifunctional neuronal adhesion molecule L1, are associated with neurodevelopmental disorders including X-linked hydrocephalus and mental retardation. Some amino acid substitutions in various extracellular domains of L1 are known to affect posttranslational processing of the protein or its homophilic and heterophilic interactions. It is largely unknown, however, how these mutations result in neurodevelopmental disturbances and whether the effects of mutations on neurodevelopment can be modeled in vitro. We stably expressed full-length human wild type L1 and the known pathogenic missense mutations I179S, R184W, Y194C, and C264Y in NIH-3T3 cells. L1 protein synthesis, glycosylation pattern, and subcellular localization were analyzed. Neurite outgrowth of primary murine cerebellar neurons was measured after 23 hrs of co-cultivation using transfected NIH-3T3 cells as substrate. Like wild type L1, L1 protein with I179S or Y194C mutations was localized on the surface of the transfected substrate cells, but this was not the case with R184W or C264Y mutations. All four mutations were associated with reduced stimulation of neurite outgrowth. Measurement of neurite outgrowth on transfected substrate cells may be a suitable model for studying neurodevelopmental disturbances.
KW - 3T3 Cells
KW - Animals
KW - Binding Sites
KW - Cerebellum
KW - Cloning, Molecular
KW - DNA, Complementary
KW - Genetic Vectors
KW - Humans
KW - Mice
KW - Mutation
KW - Mutation, Missense
KW - Neural Cell Adhesion Molecule L1
KW - Neurites
KW - Neurons
KW - Transfection
U2 - 10.1002/humu.9096
DO - 10.1002/humu.9096
M3 - SCORING: Journal article
C2 - 12442287
VL - 20
SP - 481
EP - 482
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 6
ER -