Department of Molecular Embryology, Max Planck Institute of Immunology, Freiburg, Germany.
Nat Neurosci. 2012 Jun 17;15(7):962-9. doi: 10.1038/nn.3139.
Temporal regulation of embryonic neurogenesis is controlled by hypostable transcription factors. The mechanism of the process is unclear. Here we show that the RNase III Drosha and DGCR8 (also known as Pasha), key components of the microRNA (miRNA) microprocessor, have important functions in mouse neurogenesis. Loss of microprocessor in forebrain neural progenitors resulted in a loss of stem cell character and precocious differentiation whereas Dicer deficiency did not. Drosha negatively regulated expression of the transcription factors Neurogenin 2 (Ngn2) and NeuroD1 whereas forced Ngn2 expression phenocopied the loss of Drosha. Neurog2 mRNA contains evolutionarily conserved hairpins with similarities to pri-miRNAs, and associates with the microprocessor in neural progenitors. We uncovered a Drosha-dependent destabilization of Neurog2 mRNAs consistent with microprocessor cleavage at hairpins. Our findings implicate direct and miRNA-independent destabilization of proneural mRNAs by the microprocessor, which facilitates neural stem cell (NSC) maintenance by blocking accumulation of differentiation and determination factors.
胚胎神经发生的时间调控受稳定转录因子控制。其过程的机制尚不清楚。在这里，我们发现 RNA 酶 III Drosha 和 DGCR8（也称为 Pasha），是 microRNA（miRNA）微处理器的关键组成部分，在小鼠神经发生中具有重要功能。前脑神经祖细胞中微处理器的缺失导致干细胞特性丧失和早熟分化，而 Dicer 缺失则不会。Drosha 负调控转录因子 Neurogenin 2（Ngn2）和 NeuroD1 的表达，而强制表达 Ngn2 则可模拟 Drosha 的缺失。Neurog2 mRNA 包含与 pri-miRNAs 具有相似性的进化上保守的发夹结构，并且与神经祖细胞中的微处理器相关联。我们发现 Drosha 依赖性 Neurog2 mRNA 不稳定性，这与发夹处的微处理器切割一致。我们的研究结果表明，微处理器通过阻止分化和决定因子的积累，直接且不依赖 miRNA 对前神经 mRNA 进行不稳定性调控，从而促进神经干细胞（NSC）的维持。
