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J. Biol. Chem., Vol. 281, Issue 18, 12468-12474, May 5, 2006

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Fox-2 Splicing Factor Binds to a Conserved Intron Motif to Promote Inclusion of Protein 4.1R Alternative Exon 16^*

Julie L. Ponthier¹, Christina Schluepen¹, Weiguo Chen, Robert A. Lersch, Sherry L. Gee, Victor C. Hou, Annie J. Lo, Sarah A. Short, Joel A. Chasis, John C. Winkelmann, and John G. Conboy²

From the Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 and the Division of Hematology-Oncology, Department of Internal Medicine, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Activation of protein 4.1R exon 16 (E16) inclusion during erythropoiesis represents a physiologically important splicing switch that increases 4.1R affinity for spectrin and actin. Previous studies showed that negative regulation of E16 splicing is mediated by the binding of heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins to silencer elements in the exon and that down-regulation of hnRNP A/B proteins in erythroblasts leads to activation of E16 inclusion. This article demonstrates that positive regulation of E16 splicing can be mediated by Fox-2 or Fox-1, two closely related splicing factors that possess identical RNA recognition motifs. SELEX experiments with human Fox-1 revealed highly selective binding to the hexamer UGCAUG. Both Fox-1 and Fox-2 were able to bind the conserved UGCAUG elements in the proximal intron downstream of E16, and both could activate E16 splicing in HeLa cell co-transfection assays in a UGCAUG-dependent manner. Conversely, knockdown of Fox-2 expression, achieved with two different siRNA sequences resulted in decreased E16 splicing. Moreover, immunoblot experiments demonstrate mouse erythroblasts express Fox-2. These findings suggest that Fox-2 is a physiological activator of E16 splicing in differentiating erythroid cells in vivo. Recent experiments show that UGCAUG is present in the proximal intron sequence of many tissue-specific alternative exons, and we propose that the Fox family of splicing enhancers plays an important role in alternative splicing switches during differentiation in metazoan organisms.

Received for publication, October 25, 2005 , and in revised form, March 10, 2006.

^* This work was supported by National Institutes of Health Grants HL45182 and DK32094, by a research fellowship from the German Research Foundation (DFG) (to C. S.), and by the Director, Office of Biological and Environmental Research, United States Dept. of Energy, under Contract DE-AC03-76SF00098. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Lawrence Berkeley National Laboratory, Life Sciences Division, 1 Cyclotron Rd., Mail-stop 74-157, Berkeley, CA 94720. Tel.: 510-486-6973; Fax: 510-486-6746; E-mail: jgconboy{at}lbl.gov.

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