Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Neural Dev. 2012 May 3;7:15. doi: 10.1186/1749-8104-7-15.
In the developing vertebrate nervous system elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells. The mechanisms that limit Notch activity to balance formation of neurons and glia from neural precursors are poorly understood.
By screening for mutations that disrupt oligodendrocyte development in zebrafish we found one allele, called vu56, that produced excess oligodendrocyte progenitor cells (OPCs). Positional cloning revealed that the vu56 allele is a mutation of fbxw7, which encodes the substrate recognition component of a ubiquitin ligase that targets Notch and other proteins for degradation. To investigate the basis of the mutant phenotype we performed in vivo, time-lapse imaging, which revealed that the increase in OPC number resulted from production of extra OPCs by ventral spinal cord precursors and not from changes in OPC proliferation or death. Notch signaling activity was elevated in spinal cord precursors of fbxw7 mutant zebrafish and inhibition of Notch signaling suppressed formation of excess OPCs.
Notch signaling promotes glia cell formation from neural precursors in vertebrate embryos. Our data indicate that Fbxw7 helps attenuate Notch signaling during zebrafish neural development thereby limiting the number of OPCs.
在脊椎动物神经系统的发育过程中，Notch 信号活性的升高可以阻断神经发生并促进神经胶质细胞的形成。然而，限制 Notch 活性以平衡神经元和神经胶质细胞从神经前体细胞中形成的机制尚不清楚。
通过筛选斑马鱼中破坏少突胶质细胞发育的突变体，我们发现了一个等位基因，称为 vu56，它产生了过多的少突胶质前体细胞（OPC）。定位克隆表明，vu56 等位基因是 fbxw7 的突变，它编码泛素连接酶的底物识别组件，该酶可将 Notch 和其他蛋白质靶向降解。为了研究突变表型的基础，我们进行了体内、实时成像，结果表明 OPC 数量的增加是由于腹侧脊髓前体细胞产生了额外的 OPC，而不是 OPC 增殖或死亡的变化。在 fbxw7 突变体斑马鱼的脊髓前体细胞中，Notch 信号活性升高，抑制 Notch 信号可抑制过多 OPC 的形成。
Notch 信号在脊椎动物胚胎中促进神经前体细胞向胶质细胞的形成。我们的数据表明，Fbxw7 在斑马鱼神经发育过程中有助于减弱 Notch 信号，从而限制 OPC 的数量。
