Elevated SHH signaling in the dorsal

Elevated SHH signaling in the dorsal V-SVZ regulates the production of oligodendrocyte progenitor cells in the corpus callosum while SHH signaling in the ventral V-SVZ controls the production of specific neuron subtypes destined for the OB (Tong et al., 2015). We previously observed that PTC deletion in NSCs decreases the ability of precursor cells to give rise to oligodendrocytes (Ferent et al., 2014). It would be interesting to evaluate the effect of long-term PTC deletion on the production of specific neurons in the OB (Tong et al., 2015). PTC invalidation in multipotent stem cells of human GFAP-Cre;PTC mice during embryogenesis leads to medulloblastomas that develop when the cells have committed to the neuronal lineage (Yang et al., 2008). Our data demonstrate that PTC invalidation in NSCs increases the pool of qNSCs over the long term without the development of tumors, which demonstrates that the tumor-suppressor gene function of PTC (Goodrich et al., 1997) depends on the NSC context. In sum, we uncovered that activation of the SHH pathway increases the pool of qNSCs over a long time period, thus demonstrating that active SHH signaling maintains V-SVZ cell quiescence. This is reminiscent of the recent role attributed to active Hh signaling engaged in an epithelial-mesenchymal regulatory loop to maintain quiescence under normal homeostasis in the adult lung (Peng et al., 2015). Sustained SHH signaling in NSCs presumably occurs during physiological or pathological conditions, for instance, pharmacological activation of Smo using specific small-molecule modulators (Ruat et al., 2014), when SHH protein is induced (Ferent et al., 2013), or as a result of inactivating PTC or activating Smo mutations. Thus, it will be important to further identify the status of qNSCs and aNSCs in such conditions, as well as determine their effects on neurogenesis, tumor formation, and casein kinase 2 inhibitor repair. Of note, this accumulated pool of qNSCs has trouble replenishing the SVZ after antimitotic treatment (Ferent et al., 2014). Thus, it should be of great interest to address whether the increased pool of qNSCs observed upon SHH activation can be further manipulated in the older animal to restore impaired neurogenesis (Daynac et al., 2013) as observed with anti-transforming growth factor β treatment (Pineda et al., 2013; Daynac et al., 2014). Importantly, SHH signaling also regulates NSC mobilization toward demyelinated lesions, and inhibition of GLI1 was shown to mobilize NSCs for remyelination (Samanta et al., 2015). Although the phenotype in qNSCs and aNSCs was not reported in this study, it indicates that multiple levels of SHH-GLI signaling regulate more than just proliferation and highlights the importance of determining the state of NSCs and their progeny. Altogether, our data highlight the complex role of the SHH pathway in NSC regulation and its importance for adult neurogenesis, and the need for further understanding of the mechanisms associated with brain tumor formation and brain repair.
Experimental Procedures
Author Contributions M.D.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; L.T.: collection and assembly of data; H.F.: collection of data, data analysis and interpretation; M.M.: collection and assembly of data; L.R.G.: collection and assembly of data; H.H.: characterization of YFP-PTC+/+ and YFP-PTC−/− mice; F.D.B.: conception and design, data analysis, interpretation, and manuscript writing; M.R.: conception, design, data analysis, interpretation, and manuscript writing.
Acknowledgments We thank Prof. M. Götz (Helmholtz Zentrum, Munich) for Glast-CreERT2 and S. Picaud (NeuroPSI, Gif/Yvette) for the mice used for initial breeding, Prof. T. Jessel (Columbia University) for R26R-YFP/+ mouse lines, and E. Desale and T. Durand (TAAM, CNRS UPS44, Orléans) for expert technical assistance. We are indebted to C. Joubert, V. Neuville, J. Tilliet, and the staff of the animal facilities, I. Baijer and N. Dechamps for cell sorting, and T. Kortulewski for imaging. L.T. is the recipient of a doctoral fellowship from the Ministère de la Recherche. This work was supported by grants from La Ligue contre le Cancer (Comité de l’Essonne), Fondation Association pour la Recherche contre le Cancer (ARC) and CNRS to M.R., and Électricité de France (EDF) to F.B.