Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids.
Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids.
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DOI：
10.3389/fncel.2014.00098
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发表时间：
2014
影响因子：
5.3
通讯作者：
Tirone F
中科院分区：
文献类型：
--
作者：
Farioli-Vecchioli S;Ceccarelli M;Saraulli D;Micheli L;Cannas S;D'Alessandro F;Scardigli R;Leonardi L;Cinà I;Costanzi M;Mattera A;Cestari V;Tirone F
骨形态发生蛋白（BMPs）和Notch通路调节心室下带（SVZ）干细胞的静止和自我更新，SVZ是一个成人神经源性生态位。在这里，我们分析了Tis21 (Btg2/PC3)，一个调节成年SVZ干细胞和祖细胞增殖和分化的基因在这些通路的交叉点上的作用。在tis21缺失的SVZ和培养的神经球中，我们观察到BMP4及其效应物Smad1/8的表达明显下降，而Notch抗神经介质Hes1/5和碱性螺旋-环-螺旋（bHLH）抑制剂Id1-3的表达增加。与此一致，前膜bHLH基因NeuroD1的表达下降。此外，细胞周期蛋白D1/2、A2和E强烈上调。因此，在SVZ中，Tis21激活BMP通路，抑制Notch通路和细胞周期。相应的，tis21缺失的SVZ干细胞数量大幅增加；尽管如此，增殖的神经母细胞减少了，而有丝分裂后的神经母细胞却矛盾地在SVZ中积累，不能沿着吻侧迁移流迁移到嗅球。然而，神经母细胞从SVZ外植体迁移的能力并未受到影响，这表明由于末梢分化的缺陷，tis21缺失的神经母细胞不会迁移到嗅球。值得注意的是，BMP4的添加或Id3的沉默挽救了在Tis21缺失的神经球中观察到的分化缺陷，这表明它们介导了Tis21的促分化作用。tis21缺失嗅球中颗粒神经元数量的减少导致嗅觉检测阈值的缺陷，但对嗅觉记忆没有影响，这也表明在嗅觉回路中，新的颗粒神经元在气味敏感性而不是记忆中起主要作用。
Bone morphogenic proteins (BMPs) and the Notch 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 Tis21 (Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. 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. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. 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. 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. 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 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.
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影响因子：
5.3
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通讯作者：
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