Kolaj Adelaida, Zahr Siraj K, Wang Beatrix S, Krawec Taylor, Kazan Hilal, Yang Guang, Kaplan David R, Miller Freda D
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada.
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada.
Cell Rep. 2023 Mar 28;42(3):112242. doi: 10.1016/j.celrep.2023.112242. Epub 2023 Mar 15.
Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally primed to differentiate and that the primed mRNAs are associated with the translational repressor 4E-T. 4E-T also broadly associates with other NPC mRNAs encoding transcriptional regulators, and these are preferentially depleted from ribosomes, consistent with repression. By contrast, a second translational regulator, Cpeb4, associates with diverse target mRNAs that are largely ribosome associated. The 4E-T-dependent mRNA association is functionally important because 4E-T knockdown or conditional knockout derepresses proneurogenic mRNA translation and perturbs maintenance versus differentiation of early postnatal NPCs in culture and in vivo. Thus, early postnatal NPCs are primed to differentiate, and 4E-T regulates the balance between cell genesis and stem cell expansion by sequestering and repressing mRNAs encoding transcriptional regulators.
在此，我们探讨发育中的前体细胞如何在组织生长的细胞生成与成体干细胞库的建立之间维持平衡，重点关注出生后前脑的神经前体细胞（NPC）。我们发现这些NPC在转录上已做好分化的准备，且这些已做好准备的mRNA与翻译抑制因子4E-T相关联。4E-T还广泛地与其他编码转录调节因子的NPC mRNA相关联，并且这些mRNA优先从核糖体上耗尽，这与抑制作用一致。相比之下，另一种翻译调节因子Cpeb4与多种主要与核糖体相关的靶mRNA相关联。依赖4E-T的mRNA关联在功能上很重要，因为敲低4E-T或进行条件性敲除会解除对神经源性mRNA翻译的抑制，并扰乱出生后早期NPC在体外和体内培养时维持与分化之间的平衡。因此，出生后早期的NPC已做好分化的准备，而4E-T通过隔离和抑制编码转录调节因子的mRNA来调节细胞生成与干细胞扩增之间的平衡。
