However, recent work also indicates that the inhibition of BMP signaling – by ablating Smad4, an effector of BMP4 – is required for the generation of type A neuroblast cells ( Colak et al., 2008). Moreover, ependymal cells release the protein Noggin that may promote SVZ neurogenesis by antagonizing BMP signaling ( Lim et al., 2000). BMPs have been described to play a proastrocytic role by inhibiting neurogenesis when added to cultured SVZ neural stem cells and during embryonic development. These include Notch, Sonic hedgehog ( Shh), and bone morphogenic proteins ( BMPs). Several morphogens and genes control the proliferation and maturation of stem cells and neuroblasts in the SVZ. Indeed, type B GFAP-positive neural stem cells in the SVZ are relatively quiescent, as they are less susceptible to antimitotic treatment ( Doetsch et al., 1999). These type C cells in turn generate migrating neuroblasts, which are negative for GFAP but express Dlx2, PSA-NCAM (polysialylated neural adhesion cell molecule) and doublecortin (DCX type A cells Colak et al., 2008). These are a glial fibrillary acidic protein-positive (GFAP) subset of astrocytes, termed type B cells ( Doetsch et al., 1999), which give rise to rapidly proliferating transient amplifying cells which are GFAP-negative and express the transcription factors of the Dlx family (type C cells Doetsch et al., 2002). According to a prevailing hypothesis, the new neurons in the SVZ are generated by resident radial glia-like cells that represent quiescent neural stem cells (reviewed by Alvarez-Buylla and Lim, 2004). The subventricular zone (SVZ) of the lateral ventricles is one of the two neurogenic niches, together with the dentate gyrus of the hippocampus, where new neurons are continuously generated throughout adulthood ( Zhao et al., 2008). The reduced number of granule neurons in the Tis21-null olfactory bulb led to a defect in olfactory detection threshold, without effect on olfactory memory, also suggesting that within olfactory circuits new granule neurons play a primary role in odor sensitivity rather than in memory. Notably, BMP4 addition or Id3 silencing rescued the defective differentiation observed in Tis21-null neurospheres, indicating that they mediate the Tis21 pro-differentiative action. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that Tis21-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Correspondingly, the Tis21-null SVZ stem cells greatly increased nonetheless, the proliferating neuroblasts diminished, whereas the post-mitotic neuroblasts paradoxically accumulated in SVZ, failing to migrate along the rostral migratory stream to the olfactory bulb. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. In Tis21-null SVZ and cultured neurospheres, we observed a strong decrease in the expression of BMP4 and its effectors Smad1/8, while the Notch anti-neural mediators Hes1/5 and the basic helix-loop-helix (bHLH) inhibitors Id1-3 increased. Here we analyze the role at the intersection of these pathways of Tis21 ( Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells.
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