L1 cell adhesion molecule (L1CAM), an adhesion/signaling protein encoded by a gene target of the transcription repressor RE-1-Silencing Transcription factor (REST), is expressed in two alternatively spliced isoforms. The full-length isoform, typical of low-REST neural cells, plays key roles in survival/migration, outgrowth/fasciculation/regeneration of axons, synaptic plasticity; the isoform missing two mini-exons, abundant in a few high-REST non-neural cells, maintains some effect on migration and proliferation. To investigate whether and how L1CAM alternative splicing depends on REST we used neural cell models expressing low or high levels of REST (PC12, SH-SY5Y, differentiated NT2/D1 and primary neurons transduced or not with REST). The short isoform was found to rise when the low-REST levels of neural cells were experimentally increased, while the full-length isoform increased in high-REST cells when the repressor tone was attenuated. These results were due to Nova2, a neural cell-specific splicing factor shown here to be repressed by REST. REST control of L1CAM occurs therefore by two mechanisms, transcription and alternative splicing. The splicing mechanism, affecting not only L1CAM but all Nova2 targets (∼7% of brain-specific splicing, including the mRNAs of other adhesion and synaptic proteins) is expected to be critical during development and important also for the structure and function of mature neural cells.
Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells / J. Mikulak, S. Negrini, A. Klajn, R. D'Alessandro, D. Mavilio, J. Meldolesi. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 120:5(2012 Mar), pp. 699-709.
|Titolo:||Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells|
NEGRINI, SARA (Secondo)
MAVILIO, DOMENICO (Penultimo)
|Parole Chiave:||β-catenin; NT2/D1 cells; PC12 cells; primary neurons; REST transfection/transduction; transcription|
|Settore Scientifico Disciplinare:||Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio|
Settore MED/04 - Patologia Generale
Settore MED/26 - Neurologia
|Data di pubblicazione:||mar-2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/j.1471-4159.2011.07626.x|
|Appare nelle tipologie:||01 - Articolo su periodico|