Division of Biosciences, Institute of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6XA, UK.
Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
Nat Commun. 2024 Jun 6;15(1):4819. doi: 10.1038/s41467-024-49139-7.
Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.
神经元分化需要构建复杂的细胞内结构，因此需要协调调控特定基因。RNA 结合蛋白 (RBPs) 在这种调控中起着关键作用。然而，虽然已经深入研究了它们对单个 mRNA 的作用，但协调基因表达程序以塑造神经元形态的机制还知之甚少。为了解决这个问题，我们研究了模式 RBP IMP1（IGF2BP1）如何在人类神经元分化过程中选择和调节其 RNA 靶标。我们进行了系统和分子分析的组合，揭示了 IMP1 从发育上过渡到并直接调节编码微管网络关键调节因子的 mRNA 的表达，微管网络是神经元形态的关键组成部分。此外，我们还表明，m6A 甲基化在从神经前体细胞到神经元的发育转变过程中驱动特定 IMP1 mRNA 靶标的选择及其蛋白质表达，为靶标选择性的开始提供了一个分子原理。
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