The Francis Crick Institute, London, United Kingdom.
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
PLoS Biol. 2021 Nov 12;19(11):e3001450. doi: 10.1371/journal.pbio.3001450. eCollection 2021 Nov.
The molecular mechanisms that produce the full array of neuronal subtypes in the vertebrate nervous system are incompletely understood. Here, we provide evidence of a global temporal patterning program comprising sets of transcription factors that stratifies neurons based on the developmental time at which they are generated. This transcriptional code acts throughout the central nervous system, in parallel to spatial patterning, thereby increasing the diversity of neurons generated along the neuraxis. We further demonstrate that this temporal program operates in stem cell-derived neurons and is under the control of the TGFβ signaling pathway. Targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their functional requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal transcriptional program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning mechanisms diversifies and organizes neuronal subtypes in the vertebrate nervous system.
脊椎动物神经系统中产生各种神经元亚型的分子机制尚未完全清楚。在这里，我们提供了一个全局时间模式程序的证据，该程序包含了一系列转录因子，根据它们产生的发育时间对神经元进行分层。该转录密码在中枢神经系统中与空间模式并行作用，从而增加了沿神经轴产生的神经元的多样性。我们进一步证明，这个时间程序在干细胞衍生的神经元中起作用，并受 TGFβ 信号通路的控制。靶向干扰时间程序的组成部分 Nfia 和 Nfib，揭示了它们对产生晚期神经元亚型的功能要求。总之，我们的研究结果为神经元亚型身份的先前未被认识到的全局时间转录程序的存在提供了证据，并表明空间和时间模式机制的整合使脊椎动物神经系统中的神经元亚型多样化和组织化。
