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Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor β- and Bone Morphogenetic Protein-Independent Manner

机译:Smad7调节成人神经干/祖细胞池中转化生长因子β和骨形态发生蛋白独立的方式。

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Members of the transforming growth factor β (TGF-β) family of proteins modulate the proliferation, differentiation, and survival of many different cell types. Neural stem and progenitor cells (NPCs) in the adult brain are inhibited in their proliferation by TGF-β and by bone morphogenetic proteins (BMPs). Here, we investigated neurogenesis in a hypomorphic mouse model for the TGF-β and BMP inhibitor Smad7, with the hypothesis that NPC proliferation might be reduced due to increased TGF-β and BMP signaling. Unexpectedly, we found enhanced NPC proliferation as well as an increased number of label-retaining cells in vivo. The enhanced proliferation potential of mutant cells was retained in vitro in neurosphere cultures. We observed a higher sphere-forming capacity as well as faster growth and cell cycle progression. Use of specific inhibitors revealed that these effects were independent of TGF-β and BMP signaling. The enhanced proliferation might be at least partially mediated by elevated signaling via epidermal growth factor (EGF) receptor, as mutant cells showed higher expression and activation levels of the EGF receptor. Conversely, an EGF receptor inhibitor reduced the proliferation of these cells. Our data indicate that endogenous Smad7 regulates neural stem/progenitor cell proliferation in a TGF-β- and BMP-independent manner.
机译:蛋白质转化生长因子(TGF-β)家族的成员可调节许多不同细胞类型的增殖,分化和存活。成年大脑中的神经干细胞和祖细胞(NPC)受TGF-β和骨形态发生蛋白(BMP)抑制。在这里,我们研究了TGF-β和BMP抑制剂Smad7在亚型小鼠模型中的神经发生,并假设NPC增殖可能由于TGF-β和BMP信号传导增加而减少。出乎意料的是,我们发现增强的NPC增殖以及体内 标记保留细胞的数量增加。突变细胞增强的增殖潜能在神经球培养物中得以体外保留。我们观察到更高的球形成能力以及更快的生长和细胞周期进程。使用特异性抑制剂显示这些作用与TGF-β和BMP信号传导无关。增强的增殖可能至少部分地由通过表皮生长因子(EGF)受体的信号转导介导,因为突变细胞显示EGF受体的表达和激活水平更高。相反,EGF受体抑制剂减少了这些细胞的增殖。我们的数据表明,内源性Smad7以非TGF-β和BMP的方式调节神经干/祖细胞的增殖。

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