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

Abstract

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.

• Authors: Luigina Tagliavacca, Federico Colombo, Gabriella Racchetti, Jacopo Meldolesi
• Journal: Journal of neurochemistry (J Neurochem) Vol. 124 Issue 3 Pg. 397-409 (Feb 2013) ISSN: 1471-4159 [Electronic] England
• PMID: 22973895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Chemical References

• Neural Cell Adhesion Molecule L1
• Recombinant Proteins
• Nerve Growth Factor
• Receptor, trkA

Topics

• Animals
• Humans
• Male
• Mutation, Missense (genetics)
• Nerve Growth Factor (physiology)
• Neural Cell Adhesion Molecule L1 (genetics, physiology)
• Neurons (metabolism, pathology, physiology)
• PC12 Cells
• Rats
• Receptor, trkA (metabolism)
• Recombinant Proteins (genetics, pharmacology)
• Signal Transduction (genetics)