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Molecular and Cellular Biology, February 2007, p. 830-841, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01015-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role for Fox-1/Fox-2 in Mediating the Neuronal Pathway of Calcitonin/Calcitonin Gene-Related Peptide Alternative RNA Processing{triangledown}

Hua-Lin Zhou,1 Andrew P. Baraniak,2 and Hua Lou1,3*

Department of Genetics and Case Comprehensive Cancer Center,1 Center for RNA Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106,3 Department of Molecular Genetics and Microbiology, Center for RNA Biology, Duke University Medical Center, Durham, North Carolina 277102

Received 6 June 2006/ Returned for modification 31 July 2006/ Accepted 27 October 2006

Although multiple regulatory elements and protein factors are known to regulate the non-neuronal pathway of alternative processing of the calcitonin/calcitonin gene-related peptide (CGRP) pre-mRNA, the mechanisms controlling the neuron-specific pathway have remained elusive. Here we report the identification of Fox-1 and Fox-2 proteins as novel regulators that mediate the neuron-specific splicing pattern. Fox-1 and Fox-2 proteins function to repress exon 4 inclusion, and this effect depends on two UGCAUG elements surrounding the 3' splice site of the calcitonin-specific exon 4. In neuron-like cells, mutation of a subset of UGCAUG elements promotes the non-neuronal pattern in which exon 4 is included. In HeLa cells, overexpression of Fox-1 or Fox-2 protein decreases exon 4 inclusion. Fox-1 and Fox-2 proteins interact with the UGCAUG elements specifically and regulate splicing by blocking U2AF65 binding to the 3' splice site upstream of exon 4. We further investigated the inter-relationship between the UGCAUG silencer elements and the previously identified intronic and exonic splicing regulatory elements and found that exon 4 is regulated by an intricate balance of positive and negative regulation. These results define a critical role for Fox-1 and Fox-2 proteins in exon 4 inclusion of calcitonin/CGRP pre-mRNA and establish a regulatory network that controls the fate of exon 4.

* Corresponding author. Mailing address: Department of Genetics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Phone: (216) 368-6419. Fax: (216) 368-0491. E-mail: hxl47{at}case.edu.

{triangledown} Published ahead of print on 13 November 2006.

Molecular and Cellular Biology, February 2007, p. 830-841, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01015-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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