Ruan Xiangbin, Hu Kaining, Yang Yalan, Yang Runwei, Tseng Elizabeth, Kang Bowei, Kauffman Aileen, Zhong Rong, Zhang Xiaochang
Department of Human Genetics, The University of Chicago, Chicago, Illinois 60637.
Pacific Biosciences, Menlo Park, California 94025.
J Neurosci. 2025 Feb 12;45(7):e0822242024. doi: 10.1523/JNEUROSCI.0822-24.2024.
How master splicing regulators cross talk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq analyses of the developing neocortex uncover variable expression of the Rbfox1/2/3 genes and enriched alternative splicing events in transcription regulators, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glial progenitors induces neuronal splicing events preferentially in transcription regulators such as and Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon in Simultaneous ablation of in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform of promotes transcription, while the neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex. (The sex has not been reported to affect cortical neurogenesis in mice, and embryos of both sexes were studied without distinguishing one or the other.).
在发育中的大脑中，主剪接调节因子如何相互作用以及转录调节因子在多大程度上存在差异剪接仍不清楚。在这里，对发育中的新皮层进行细胞类型特异性RNA测序分析，发现Rbfox1/2/3基因的可变表达以及转录调节因子中丰富的可变剪接事件，这些事件改变了蛋白质异构体或诱导了无义介导的mRNA降解。放射状胶质祖细胞中Rbfox蛋白的瞬时表达优先在转录调节因子（如 和 ）中诱导神经元剪接事件。令人惊讶的是，Rbfox蛋白促进在 中包含一个哺乳动物特有的可变外显子和一个以前未描述的毒性外显子。新皮层中 的同时缺失会下调神经元异构体并破坏放射状神经元迁移。此外， 的祖细胞异构体促进 转录，而 的神经元异构体促进神经元分化。这些观察结果表明，转录调节因子在发育中的新皮层的细胞类型之间存在差异剪接。（尚未报道性别会影响小鼠的皮层神经发生，因此对两性胚胎进行了研究，未区分性别。）
