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J. Biol. Chem., Vol. 283, Issue 12, 7531-7541, March 21, 2008

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Post-transcriptional Regulation of Neuro-oncological Ventral Antigen 1 by the Neuronal RNA-binding Proteins ELAV^*

Antonia Ratti¹, Claudia Fallini, Claudia Colombrita, Alessia Pascale, Umberto Laforenza^¶, Alessandro Quattrone^||, and Vincenzo Silani

From the Department of Neurological Sciences, "Dino Ferrari" Centre, University of Milan Medical School, IRCCS Istituto Auxologico Italiano, 20095 Cusano, Milan, the Departments of Experimental and Applied Pharmacology and ^¶Experimental Medicine, University of Pavia, 27100 Pavia, and the ^||Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, 38100 Trento, Italy

Alternative splicing of pre-mRNAs plays an important role in generating biological and functional diversity. Neuro-oncological ventral antigen 1 (Nova1) is a neuron-specific splicing factor that controls the alternative processing of a wide array of mRNAs important for synaptic activity. It is essential for the proper development of the mammalian motor system and for the survival of motoneurons. Because Nova1 gene contains putative regulatory AU-rich elements (ARE) in its highly conserved 3'-untranslated region, we investigated whether its expression is regulated by post-transcriptional mechanisms mediated by ARE-binding proteins. Among these, the neuronal ELAV (nELAV) factors are interesting candidates, because their RNA binding activity is necessary for neuronal differentiation and maintenance. By analysis of ribonucleoprotein complexes in vivo and in vitro we demonstrated that the Nova1 mRNA is a novel target of the nELAV proteins. We defined the nELAV binding site by functional experiments with luciferase reporter gene and Nova1 3'-untranslated region deletion sequences. Gene silencing and overexpression of the nELAV member HuD in motoneuronal NSC34 cells indicate that Nova1 mRNA stability and translation are positively and strongly controlled by the nELAV proteins. In addition, nELAV phosphorylation by a PKC-dependent pathway induces the recruitment of Nova1 mRNA to polysomes. Noteworthy, we found that nELAV proteins are also able to modulate Nova1 splicing activity on its target genes. Our data indicate nELAV proteins as the first factors affecting the expression and activity of the neuronal splicing regulator Nova1 and, consequently, as major candidates for the physiological modulation of Nova1-dependent processing of pre-mRNAs in neurons.

Received for publication, July 24, 2007 , and in revised form, January 23, 2008.

^* This work was supported by Italian Ministry of Health Malattie Neurodegenerative, ex Art.56, Grant 533F/N 1, 2004. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2 and Figs. S1–S4.

¹ To whom correspondence should be addressed: IRCCS Istituto Auxologico Italiano, Via Zucchi, 18, 20095 Cusano, Milan, Italy. Tel.: 39-02-619113045; Fax: 39-02-619113033; E-mail: antonia.ratti{at}unimi.it.

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