Dori Amir, Cohen Jonathan, Silverman William F, Pollack Yaakov, Soreq Hermona
Department of Neurosurgery, Soroka University Medical Center, Beer-Sheva, Israel.
Cereb Cortex. 2005 Apr;15(4):419-30. doi: 10.1093/cercor/bhh145.
Proliferation and differentiation of mammalian central nervous system progenitor cells involve concertedly controlled transcriptional and alternative splicing modulations. Searching for the developmental implications of this programming, we manipulated specific acetylcholinesterase (AChE) splice variants in the embryonic mouse brain. In wild type mice, 'synaptic' AChE-S appeared in migrating neurons, whereas the C-terminus cleaved off the stress-induced AChE-R variant associated with migratory radial glial fibers. Antisense suppression of AChE-R reduced neuronal migration, allowing increased proliferation of progenitor cells. In contrast, transgenic overexpression of AChE-R was ineffective, whereas transgenic excess of enzymatically active AChE-S or inactive AChE-Sin suppressed progenitors proliferation alone or both proliferation and neuronal migration, respectively. Our findings attribute to alternative splicing events an interactive major role in neocortical development.
哺乳动物中枢神经系统祖细胞的增殖和分化涉及协同控制的转录和可变剪接调节。为了探究这种编程的发育意义，我们在胚胎小鼠大脑中操纵了特定的乙酰胆碱酯酶（AChE）剪接变体。在野生型小鼠中，“突触型”AChE-S出现在迁移的神经元中，而与迁移的放射状神经胶质纤维相关的应激诱导型AChE-R变体的C末端被切割掉。对AChE-R的反义抑制减少了神经元迁移，使祖细胞的增殖增加。相反，AChE-R的转基因过表达无效，而具有酶活性的AChE-S或无活性的AChE-Sin的转基因过量分别单独抑制祖细胞增殖或同时抑制增殖和神经元迁移。我们的发现表明可变剪接事件在新皮层发育中起主要的交互作用。
