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THE STEM CELL NICHE

An Induction Gene Trap Screen in Neural Stem Cells Reveals an Instructive Function of the Niche and Identifies the Splicing Regulator Sam68 as a Tenascin-C-Regulated Target Gene

^aDepartment of Cell Morphology and Molecular Neurobiology, Ruhr-University Bochum, Bochum, Germany;
^bInternational Graduate School of Neuroscience, Bochum, Germany

Key Words. Extracellular matrix • RNA binding protein • Alternative splicing • Signal transducer and activator of RNA • Forebrain development

Correspondence: Correspondence: Alexander von Holst, Ph.D., Department for Cell Morphology and Molecular Neurobiology, NDEF 05/339, Universitaetsstrasse 150, D-44780 Bochum, Germany. Telephone: 49-[0]-234-32-25812; Fax: 49-[0]-234-32-14313; e-mail: Alexander.vonHolst{at}ruhr-uni-bochum.de; or Prof. Dr. Andreas Faissner, Department for Cell Morphology and Molecular Neurobiology, NDEF 05/594, Universitaetsstrasse 150, D-44780 Bochum, Germany. Telephone: 49-[0]-234-32-23851; Fax: 49-[0]-234-32-14313; e-mail: Andreas.Faissner{at}ruhr-uni-bochum.de

Received on January 3, 2008; accepted for publication on July 2, 2008.

First published online in STEM CELLS EXPRESS  July 10, 2008.

Neural stem cells (NSCs) reside in a niche that abounds in extracellular matrix (ECM) molecules. The ECM glycoprotein tenascin-C (Tnc) that occurs in more than 25 isoforms represents a major constituent of the privileged NSC milieu. To understand its role for NSCs, the induction gene trap technology was successfully applied to mouse embryonic NSCs, and a library of more than 500 NSC lines with independent gene trap vector integrations was established. Our pilot screen identified Sam68 as a target of Tnc signaling in NSCs. The Tnc-mediated downregulation of Sam68, which we found expressed at low levels in the niche along with Tnc, was independently confirmed on the protein level. Sam68 is a multifunctional RNA-binding protein, and its potential significance for cultured NSCs was studied by overexpression. Increased Sam68 levels caused a marked reduction in NSC cell proliferation. In addition, Sam68 is a signal-dependent regulator of alternative splicing, and its overexpression selectively increased the larger Tnc isoforms, whereas a mutated phosphorylation-deficient Sam68 variant did not. This emphasizes the importance of Sam68 for NSC biology and implicates an instructive rather than a purely permissive role for Tnc in the neural stem cell niche.

Disclosure of potential conflicts of interest is found at the end of this article.

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