Acta Neuropathol (2014) 127:605–607 DOI 10.1007/s00401-014-1258-2

Correspondence

Wnt/β‑catenin signaling inhibits the Shh pathway and impairs tumor growth in Shh‑dependent medulloblastoma Julia Pöschl · Martin Bartels · Jasmin Ohli · Edoardo Bianchi · Konstantin Kuteykin‑Teplyakov · Daniel Grammel · Julia Ahlfeld · Ulrich Schüller 

Received: 7 January 2014 / Revised: 4 February 2014 / Accepted: 5 February 2014 / Published online: 15 February 2014 © Springer-Verlag Berlin Heidelberg 2014

30 % of medulloblastomas show activated Sonic-hedgehog (Shh) signaling. Shh is crucial for the proliferation of cerebellar granule neuron precursors (GNPs) [12], but constitutive activation of the Shh pathway in GNPs leads to medulloblastoma [10]. In contrast, canonical Wnt/β-catenin signaling is required for the maturation of GNPs, and constitutive activation of this pathway causes significant proliferation deficits [6]. To develop new therapeutic strategies for patients with Shh-medulloblastoma, we asked whether the physiological roles of Wnt/β-catenin signaling can be utilized to treat Shhmedulloblastomas that have developed from GNPs. SmoM2Fl/+ [7], Ctnnb1(ex3)Fl/+ [4], or SmoM2Fl/+ Ctnnb1(ex3)Fl/+ cerebellar GNPs were cultured as described [6] and transduced with Cre-IRES-GFP viruses. Cre treatment of SmoM2Fl/+ cerebellar GNPs led to a 2.6-fold proliferation increase due to active Shh signaling (Fig. 1a, p = 0.008). Wnt pathway activation in Ctnnb1(ex3)Fl/+ GNPs reduced proliferation to 52 % (Fig. 1a, p  = 0.029). Importantly, Wnt-activation significantly decreased oncogenic GNP proliferation driven by SmoM2 (Ctnnb1(ex3)Fl/+SmoM2Fl/+ condition, Fig. 1a, p  = 0.028), and cells reached proliferation levels similar to the wild type. Thus, the proliferation of Shh-medulloblastoma cells may be blocked through canonical Wnt signaling. These results extend previous

Electronic supplementary material  The online version of this article (doi:10.1007/s00401-014-1258-2) contains supplementary material, which is available to authorized users. J. Pöschl · M. Bartels · J. Ohli · E. Bianchi · K. Kuteykin‑Teplyakov · D. Grammel · J. Ahlfeld · U. Schüller (*)  Center for Neuropathology and Prion Research, LudwigMaximilians-University, Feodor‑Lynen‑Strasse 23, 81377 Munich, Germany e-mail: [email protected]‑muenchen.de

studies showing inhibitory effects of Wnt3a through noncanonical Wnt-signaling on GNPs [1]. Next, we introduced a Ctnnb1(ex3)Fl/+ allele into Math1-cre::SmoM2Fl/+ mice, a model for Shh-medulloblastoma [10]. Activation of the Shh pathway in Math1-positive GNPs resulted in a thickened external granule cell layer (EGL) and medulloblastoma (Fig. 1b, c, Suppl. Fig. 1a). Additional activation of the Wnt-pathway (Math1-cre::SmoM2Fl/+Ctnnb1(ex3)Fl/+ mice) notably reduced growth of medulloblastoma and resulted in decreased cerebellar size (Fig. 1b, d, Suppl. Fig. 1a). GNPs within the cochlear nucleus also form Shh-dependent medulloblastoma in Math1-cre::SmoM2Fl/+ mice [3]. Brain stem tumors generated in Math1-cre::SmoM2Fl/+Ctnnb1(ex3)Fl/+ mice were substantially smaller and showed decreased proliferation in an analogous manner when compared to tumors in Math1-cre::SmoM2Fl/+ mice (Suppl. Fig. 1b). Importantly, Math1-cre::SmoM2Fl/+Ctnnb1(ex3)Fl/+ mice (n  = 16) survived significantly longer than Math1cre::SmoM2Fl/+ animals (n  = 53, p 

β-catenin signaling inhibits the Shh pathway and impairs tumor growth in Shh-dependent medulloblastoma.

β-catenin signaling inhibits the Shh pathway and impairs tumor growth in Shh-dependent medulloblastoma. - PDF Download Free
374KB Sizes 0 Downloads 0 Views