Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells

Authors

  • Joanna Mikulak,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. CellDiff Excellence Research Center, Division of Neuroscience and Italian Institute of Technology Network, Research Unit of Molecular Neuroscience and San Raffaele Scientific Institute, Milan, Italy
    3. Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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  • Sara Negrini,

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. CellDiff Excellence Research Center, Division of Neuroscience and Italian Institute of Technology Network, Research Unit of Molecular Neuroscience and San Raffaele Scientific Institute, Milan, Italy
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  • Andrijana Klajn,

    1. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, Belgrade, Serbia
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  • Rosalba D’Alessandro,

    1. S. De Bellis Scientific Institute, Castellana Grotte, Bari, Italy
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  • Domenico Mavilio,

    1. Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Clinico Humanitas, Rozzano, Milan, Italy
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  • Jacopo Meldolesi

    1. Vita-Salute San Raffaele University, Milan, Italy
    2. CellDiff Excellence Research Center, Division of Neuroscience and Italian Institute of Technology Network, Research Unit of Molecular Neuroscience and San Raffaele Scientific Institute, Milan, Italy
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Address correspondence and reprint requests to Jacopo Meldolesi, MD, San Raffaele Scientific Institute, DIBIT, via Olgettina 58, 20132, Milan, Italy. E-mail: meldolesi.jacopo@hsr.it; and Joanna Mikulak, PhD, Clinical Institute Humanitas, via Manzoni 56, 20089, Rozzano, Milan, Italy. E-mail: Joanna.Mikulak@humanitasresearch.it

Abstract

J. Neurochem (2012) 120, 699–709.

Abstract

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.

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