TY - JOUR
T1 - L1 mediated homophilic binding and neurite outgrowth are modulated by alternative splicing of exon 2
AU - Jacob, Jeffrey
AU - Haspel, Jeffrey
AU - Kane-Goldsmith, Noriko
AU - Grumet, Martin
PY - 2002
Y1 - 2002
N2 - The neural cell adhesion molecule (CAM) L1 is a member of the immunoglobulin superfamily that has been implicated in neuronal adhesion, neurite outgrowth, and axon guidance. The clinical importance of L1 is illustrated by pathological mutations that lead to hydrocephalus, mental retardation, motor defects, and early mortality. The L1 gene is composed of 28 exons, including exons 2 and 27 that are spliced alternatively, and mutations in exon 2 are associated with severe neurological abnormalities in humans. To elucidate the role of L1 exon 2, a recombinant Fc fusion protein called Δ2L1 was constructed lacking the second exon in the extracellular domain of L1. When bound to fluorescent beads, L1 exhibited homophilic binding while Δ2L1 did not. However, L1 beads coaggregated with the Δ2L1 beads. Similarly, in cell binding studies, L1 bound to L1 and Δ2L1 did not bind to Δ2L1 but it bound moderately to L1. Given the reduced binding of Δ2L1, we tested its effect on neurons. By comparison to L1, a lower percentage of dissociated neurons extended neurites on Δ2L1, and there was a modest decrease in the length of the neurites that grew. Neurite outgrowth from reaggregated neurons was much less robust on Δ2L1 than on L1. The combined results indicate that Δ2L1 does not bind homophilically but it can interact with L1 containing exon 2. The reduced binding and neurite promoting activity of Δ2L1 provides an explanation for certain pathological mutations in L1 that lead to clinically apparent disease in the absence of the normal form of L1 in the nervous system.
AB - The neural cell adhesion molecule (CAM) L1 is a member of the immunoglobulin superfamily that has been implicated in neuronal adhesion, neurite outgrowth, and axon guidance. The clinical importance of L1 is illustrated by pathological mutations that lead to hydrocephalus, mental retardation, motor defects, and early mortality. The L1 gene is composed of 28 exons, including exons 2 and 27 that are spliced alternatively, and mutations in exon 2 are associated with severe neurological abnormalities in humans. To elucidate the role of L1 exon 2, a recombinant Fc fusion protein called Δ2L1 was constructed lacking the second exon in the extracellular domain of L1. When bound to fluorescent beads, L1 exhibited homophilic binding while Δ2L1 did not. However, L1 beads coaggregated with the Δ2L1 beads. Similarly, in cell binding studies, L1 bound to L1 and Δ2L1 did not bind to Δ2L1 but it bound moderately to L1. Given the reduced binding of Δ2L1, we tested its effect on neurons. By comparison to L1, a lower percentage of dissociated neurons extended neurites on Δ2L1, and there was a modest decrease in the length of the neurites that grew. Neurite outgrowth from reaggregated neurons was much less robust on Δ2L1 than on L1. The combined results indicate that Δ2L1 does not bind homophilically but it can interact with L1 containing exon 2. The reduced binding and neurite promoting activity of Δ2L1 provides an explanation for certain pathological mutations in L1 that lead to clinically apparent disease in the absence of the normal form of L1 in the nervous system.
KW - CRASH
KW - Cell adhesion molecule
KW - L1
KW - Splicing
KW - X-linked hydrocephalus
UR - http://www.scopus.com/inward/record.url?scp=0036254715&partnerID=8YFLogxK
U2 - 10.1002/neu.10052
DO - 10.1002/neu.10052
M3 - Article
C2 - 11984840
AN - SCOPUS:0036254715
SN - 0022-3034
VL - 51
SP - 177
EP - 189
JO - Journal of Neurobiology
JF - Journal of Neurobiology
IS - 3
ER -