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Molecular and Cellular Biology, January 2009, p. 201-213, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01349-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Sam68 Regulates a Set of Alternatively Spliced Exons during Neurogenesis{triangledown} ,{dagger}

Geetanjali Chawla,1,{ddagger} Chia-Ho Lin,2 Areum Han,3 Lily Shiue,4 Manuel Ares Jr.,4 and Douglas L. Black1,2*

Howard Hughes Medical Institute, University of California, Los Angeles, 6-762 MacDonald Research Laboratories, 675 Charles E. Young Drive South, Los Angeles, California 90095,1 Department of Microbiology, Immunology, and Molecular Genetics, 6-762 MacDonald Research Laboratories, Los Angeles, California 90095,2 Biomedical Engineering Interdepartmental Program, School of Engineering and Applied Science, University of California, Los Angeles, California 90095,3 Center for Molecular Biology of RNA, Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz, California 950644

Received 25 August 2008/ Accepted 9 October 2008

Sam68 (Src-associated in mitosis, 68 kDa) is a KH domain RNA binding protein implicated in a variety of cellular processes, including alternative pre-mRNA splicing, but its functions are not well understood. Using RNA interference knockdown of Sam68 expression and splicing-sensitive microarrays, we identified a set of alternative exons whose splicing depends on Sam68. Detailed analysis of one newly identified target exon in epsilon sarcoglycan (Sgce) showed that both RNA elements distributed across the adjacent introns and the RNA binding activity of Sam68 are necessary to repress the Sgce exon. Sam68 protein is upregulated upon neuronal differentiation of P19 cells, and many Sam68 RNA targets change in expression and splicing during this process. When Sam68 is knocked down by short hairpin RNAs, many Sam68-dependent splicing changes do not occur and P19 cells fail to differentiate. We also found that the differentiation of primary neuronal progenitor cells from embryonic mouse neocortex is suppressed by Sam68 depletion and promoted by Sam68 overexpression. Thus, Sam68 controls neurogenesis through its effects on a specific set of RNA targets.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, UCLA, 5-748 MacDonald Research Laboratories, 675 Charles E. Young Drive South, Los Angeles, CA 90095-1662. Phone: (310) 794-7946. Fax: (310) 206-8623. E-mail: dougb{at}microbio.ucla.edu

{triangledown} Published ahead of print on 20 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Indiana University, Jordan Hall A502, 1001 E. 3rd St., Bloomington, IN 47405.

Molecular and Cellular Biology, January 2009, p. 201-213, Vol. 29, No. 1
0270-7306/09/$08.00+0     doi:10.1128/MCB.01349-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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