Coskun V, Venkatraman G, Yang H, Rao M S, Luskin M B
Department of Cell Biology, Emory University School of Medicine, 1648 Pierce Drive, Atlanta, GA 30322, USA.
Int J Dev Neurosci. 2001 Apr;19(2):219-27. doi: 10.1016/s0736-5748(00)00092-7.
Bone morphogenetic proteins (BMPs), a group of cytokines in the TGF-beta superfamily, have complex regulatory roles in the control of neural proliferation and cell fate decision. In this study, we analyzed the potential role(s) of BMP signaling on the regulation of the proliferation and differentiation of the unique progenitor cells of the neonatal anterior subventricular zone (SVZa). Unlike other progenitor cells of the brain, SVZa progenitor cells have the capacity to divide even though they express a neuronal phenotype. In order to augment or inhibit endogenous BMP signaling, we injected into the neonatal rat SVZa replication-deficient retroviruses encoding for either the wild-type BMP receptor subtype Ia (wt-BMPR-Ia) or a mutated dominant-negative version of BMPR-Ia (dn-BMPR-Ia) in conjunction with a reporter gene, human alkaline phosphatase (AP) and perfused the pups 1, 4 and 7 days post injection. We analyzed whether changing the expression of BMPR-Ia has an effect on the spatial-temporal expression pattern of the cyclin dependent kinase inhibitor, p19(INK4d), or on the phenotype of SVZa derived cells. The results of our study confirmed and extended our previous findings that in control (non injected) animals, the rostral migratory stream (RMS), traversed by the SVZa-derived cells en route to the olfactory bulb, exhibits an anterior(high)-posterior(low) gradient of p19(INK4d) expression; p19(INK4d) expression is essentially absent in the SVZa and highest in the subependymal zone in the middle of the olfactory bulb. However, SVZa progenitor cells encoding the wt-BMPR-Ia gene express p19(INK4d) within the SVZa, suggesting that the BMPs induce SVZa cells to ectopically undergo cell cycle exit within the SVZa. Furthermore, unlike striatal SVZ progenitor cells, which acquire an astrocytic phenotype when exposed to BMPs, SVZa progenitor cells retain their neuronal commitment under augmented BMP signaling.
骨形态发生蛋白（BMPs）是转化生长因子-β超家族中的一组细胞因子，在神经增殖和细胞命运决定的控制中具有复杂的调节作用。在本研究中，我们分析了BMP信号传导在调节新生大鼠前脑室下区（SVZa）独特祖细胞增殖和分化方面的潜在作用。与大脑中的其他祖细胞不同，SVZa祖细胞即使表达神经元表型也具有分裂能力。为了增强或抑制内源性BMP信号传导，我们将编码野生型BMP受体亚型Ia（wt-BMPR-Ia）或BMPR-Ia的突变显性负性形式（dn-BMPR-Ia）的复制缺陷型逆转录病毒与报告基因人碱性磷酸酶（AP）一起注射到新生大鼠的SVZa中，并在注射后1、4和7天对幼崽进行灌注。我们分析了改变BMPR-Ia的表达是否会对细胞周期蛋白依赖性激酶抑制剂p19（INK4d）的时空表达模式或对SVZa衍生细胞的表型产生影响。我们的研究结果证实并扩展了我们之前的发现，即在对照（未注射）动物中，由SVZa衍生的细胞在前往嗅球途中穿过的吻侧迁移流（RMS）呈现出p19（INK4d）表达的前（高）-后（低）梯度；p19（INK4d）在SVZa中基本不存在，而在嗅球中部的室管膜下区最高。然而，编码wt-BMPR-Ia基因的SVZa祖细胞在SVZa内表达p19（INK4d），这表明BMPs诱导SVZa细胞在SVZa内异位进入细胞周期退出状态。此外，与纹状体SVZ祖细胞不同，纹状体SVZ祖细胞在暴露于BMPs时会获得星形胶质细胞表型，而SVZa祖细胞在增强的BMP信号传导下保留其神经元特性。
