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L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells

The L1 syndrome, a genetic disease that affects 1/30 000 newborn males, is sustained by numerous missense mutations of L1 cell adhesion molecule (L1CAM), an adhesion surface protein active also in transmembrane signaling, essential for the development and function of neurons. To investigate the cell...

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Autores principales: Tagliavacca, Luigina, Colombo, Federico, Racchetti, Gabriella, Meldolesi, Jacopo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557714/
https://www.ncbi.nlm.nih.gov/pubmed/22973895
http://dx.doi.org/10.1111/jnc.12015
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author Tagliavacca, Luigina
Colombo, Federico
Racchetti, Gabriella
Meldolesi, Jacopo
author_facet Tagliavacca, Luigina
Colombo, Federico
Racchetti, Gabriella
Meldolesi, Jacopo
author_sort Tagliavacca, Luigina
collection PubMed
description The L1 syndrome, a genetic disease that affects 1/30 000 newborn males, is sustained by numerous missense mutations of L1 cell adhesion molecule (L1CAM), an adhesion surface protein active also in transmembrane signaling, essential for the development and function of neurons. To investigate the cell biology of L1CAM, we employed a high RE1-silencing transcription (factor) clone of the pheochromocytoma PC12 line, defective in L1CAM expression and neurite outgrowth. The clone was transfected with wild-type L1CAM and four missense, disease-inducing point mutants encoding proteins distributed to the cell surface. The mutant-expressing cells, defective in adhesion to extracellular matrix proteins and in migration, exhibited unchanged proliferation. The nerve growth factor (NGF)-induced neurite outgrowth was re-established in defective clone cells transfected with the wild-type and the H210Q and I219T L1CAMs mutants, but not in the others. The stimulated outgrowth was confirmed in a second defective PC12 clone over-expressing the NGF receptor TrkA, treated with NGF and/or a recombinant L1CAM chimera. These results revealed a new function of L1CAM, a positive, robust and dose-dependent modulation of the TrkA receptor activated spontaneously or by NGF. The variable effects observed with the different L1CAM mutants suggest that this function contributes to the marked heterogeneity of symptoms and severity observed in the patients affected by the L1 syndrome.
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spelling pubmed-35577142013-01-31 L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells Tagliavacca, Luigina Colombo, Federico Racchetti, Gabriella Meldolesi, Jacopo J Neurochem Original Articles The L1 syndrome, a genetic disease that affects 1/30 000 newborn males, is sustained by numerous missense mutations of L1 cell adhesion molecule (L1CAM), an adhesion surface protein active also in transmembrane signaling, essential for the development and function of neurons. To investigate the cell biology of L1CAM, we employed a high RE1-silencing transcription (factor) clone of the pheochromocytoma PC12 line, defective in L1CAM expression and neurite outgrowth. The clone was transfected with wild-type L1CAM and four missense, disease-inducing point mutants encoding proteins distributed to the cell surface. The mutant-expressing cells, defective in adhesion to extracellular matrix proteins and in migration, exhibited unchanged proliferation. The nerve growth factor (NGF)-induced neurite outgrowth was re-established in defective clone cells transfected with the wild-type and the H210Q and I219T L1CAMs mutants, but not in the others. The stimulated outgrowth was confirmed in a second defective PC12 clone over-expressing the NGF receptor TrkA, treated with NGF and/or a recombinant L1CAM chimera. These results revealed a new function of L1CAM, a positive, robust and dose-dependent modulation of the TrkA receptor activated spontaneously or by NGF. The variable effects observed with the different L1CAM mutants suggest that this function contributes to the marked heterogeneity of symptoms and severity observed in the patients affected by the L1 syndrome. Blackwell Publishing Ltd 2013-02 2012-12-10 /pmc/articles/PMC3557714/ /pubmed/22973895 http://dx.doi.org/10.1111/jnc.12015 Text en © 2013 International Society for Neurochemistry http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Original Articles
Tagliavacca, Luigina
Colombo, Federico
Racchetti, Gabriella
Meldolesi, Jacopo
L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title_full L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title_fullStr L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title_full_unstemmed L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title_short L1CAM and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
title_sort l1cam and its cell-surface mutants: new mechanisms and effects relevant to the physiology and pathology of neural cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557714/
https://www.ncbi.nlm.nih.gov/pubmed/22973895
http://dx.doi.org/10.1111/jnc.12015
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