Nasu Makoto, Esumi Shigeyuki, Hatakeyama Jun, Tamamaki Nobuaki, Shimamura Kenji
Department of Health Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Front Cell Dev Biol. 2021 Apr 16;9:632381. doi: 10.3389/fcell.2021.632381. eCollection 2021.
Proper brain development requires precisely controlled phases of stem cell proliferation, lineage specification, differentiation, and migration. Lineage specification depends partly on concentration gradients of chemical cues called morphogens. However, the rostral brain (telencephalon) expands prominently during embryonic development, dynamically altering local morphogen concentrations, and telencephalic subregional properties develop with a time lag. Here, we investigated how progenitor specification occurs under these spatiotemporally changing conditions using a three-dimensional differentiation model. We verified the critical contributions of three signaling factors for the lineage specification of subregional tissues in the telencephalon, ventralizing sonic hedgehog (Shh) and dorsalizing bone morphogenetic proteins (BMPs) and WNT proteins (WNTs). We observed that a short-lasting signal is sufficient to induce subregional progenitors and that the timing of signal exposure for efficient induction is specific to each lineage. Furthermore, early and late progenitors possess different Shh signal response capacities. This study reveals a novel developmental mechanism for telencephalon patterning that relies on the interplay of dose- and time-dependent signaling, including a time lag for specification and a temporal shift in cellular Shh sensitivity. This delayed fate choice through two-phase specification allows tissues with marked size expansion, such as the telencephalon, to compensate for the changing dynamics of morphogen signals.
正常的大脑发育需要干细胞增殖、谱系特化、分化和迁移等阶段得到精确控制。谱系特化部分取决于称为形态发生素的化学信号的浓度梯度。然而，端脑在胚胎发育过程中显著扩张，动态改变局部形态发生素浓度，并且端脑亚区域特性的发育存在时间滞后。在这里，我们使用三维分化模型研究了在这些时空变化条件下祖细胞特化是如何发生的。我们验证了三种信号因子对端脑亚区域组织谱系特化的关键作用，即腹侧化的音猬因子（Shh）、背侧化的骨形态发生蛋白（BMPs）和WNT蛋白（WNTs）。我们观察到短暂的信号足以诱导亚区域祖细胞，并且有效诱导的信号暴露时间对每个谱系都是特定的。此外，早期和晚期祖细胞具有不同的Shh信号反应能力。这项研究揭示了一种新的端脑模式发育机制，该机制依赖于剂量和时间依赖性信号的相互作用，包括特化的时间滞后和细胞Shh敏感性的时间变化。这种通过两阶段特化的延迟命运选择使端脑等具有显著大小扩张的组织能够补偿形态发生素信号的动态变化。
