School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; Centre for Cell and Developmental Biology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
Cell Rep. 2020 Mar 17;30(11):3616-3624.e4. doi: 10.1016/j.celrep.2020.02.089.
Neural progenitors undergo temporal fate transition to generate diversified neurons in stereotyped sequence during development. However, the molecular machineries driving progenitor fate change remain unclear. Here, using the cerebellum as a platform, we demonstrate that the temporal dynamics of a dorsoventral bone morphogenetic protein (BMP)/SMAD signaling gradient orchestrates the transition from early to late phase of neurogenesis. Initially, high BMP/SMAD activity in cerebellum neural progenitors transcriptionally represses the late-born interneuron fate determinant Gsx1. As development proceeds, gradual decline in SMAD activities from ventral to dorsal progenitors progressively alleviates suppression on Gsx1 and allows transition of progenitor fate. Manipulating the BMP signaling dynamics can either lead to an immediate halt or rapid acceleration of the temporal fate switch, thus unbalancing the generation of distinct neuronal populations. Our study thus demonstrates that neural progenitors possess inherent competence to produce late-born neurons, yet identity transition is mechanistically executed by precisely timed and positioned reduction of repressors for late-fate determinants.
神经祖细胞在发育过程中经历时间命运转变，以定型序列产生多样化的神经元。然而，驱动祖细胞命运变化的分子机制尚不清楚。在这里，我们利用小脑作为平台，证明了背腹骨形态发生蛋白（BMP）/SMAD 信号梯度的时间动态协调了从早期到晚期神经发生的转变。最初，小脑神经祖细胞中高 BMP/SMAD 活性转录抑制晚期出生的中间神经元命运决定因子 Gsx1。随着发育的进行，SMAD 活性从腹侧到背侧祖细胞的逐渐下降逐渐解除对 Gsx1 的抑制，允许祖细胞命运的转变。操纵 BMP 信号转导动力学可以导致时间命运转变的立即停止或快速加速，从而破坏不同神经元群体的产生。因此，我们的研究表明，神经祖细胞具有产生晚期出生神经元的内在能力，但身份转变是通过精确计时和定位减少晚期命运决定因子的抑制剂来机械执行的。
