AUTHOR=Farioli-Vecchioli Stefano , Ceccarelli Manuela , Saraulli Daniele , Micheli Laura , Cannas Sara , D'Alessandro Francesca , Scardigli Raffaella , Leonardi Luca , Cinà Irene , Costanzi Marco , Mattera Andrea , Cestari Vincenzo , Tirone Felice 

TITLE=Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=8

YEAR=2014

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2014.00098

DOI=10.3389/fncel.2014.00098

ISSN=1662-5102

ABSTRACT=<p>Bone morphogenic proteins (BMPs) and the <italic>Notch</italic> pathway regulate quiescence and self-renewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche. Here we analyze the role at the intersection of these pathways of <italic>Tis21</italic> (<italic>Btg2/PC3</italic>), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. In <italic>Tis21</italic>-null SVZ and cultured neurospheres, we observed a strong decrease in the expression of <italic>BMP4 </italic> and its effectors <italic>Smad1/8</italic>, while the <italic>Notch</italic> anti-neural mediators <italic>Hes1/5</italic> and the basic helix-loop-helix (bHLH) inhibitors <italic>Id1-3</italic> increased. Consistently, expression of the proneural bHLH gene <italic>NeuroD1</italic> decreased. Moreover, <italic>cyclins D1/2</italic>, <italic>A2</italic>, and <italic>E</italic> were strongly up-regulated. Thus, in the SVZ <italic>Tis21</italic> activates the BMP pathway and inhibits the <italic>Notch</italic> pathway and the cell cycle. Correspondingly, the <italic>Tis21</italic>-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. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that <italic>Tis21</italic>-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Notably, BMP4 addition or <italic>Id3</italic> silencing rescued the defective differentiation observed in <italic>Tis21</italic>-null neurospheres, indicating that they mediate the <italic>Tis21</italic> pro-differentiative action. The reduced number of granule neurons in the <italic>Tis21</italic>-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.</p>