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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.

stem cells

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