The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia.
Stem Cell Reports. 2023 Mar 14;18(3):654-671. doi: 10.1016/j.stemcr.2023.01.010. Epub 2023 Feb 16.
Inhibitory neurons originating from the ventral forebrain are associated with several neurological conditions. Distinct ventral forebrain subpopulations are generated from topographically defined zones; lateral-, medial- and caudal ganglionic eminences (LGE, MGE and CGE), yet key specification factors often span across developing zones contributing to difficulty in defining unique LGE, MGE or CGE profiles. Here we use human pluripotent stem cell (hPSC) reporter lines (NKX2.1-GFP and MEIS2-mCherry) and manipulation of morphogen gradients to gain greater insight into regional specification of these distinct zones. We identified Sonic hedgehog (SHH)-WNT crosstalk in regulating LGE and MGE fate and uncovered a role for retinoic acid signaling in CGE development. Unraveling the influence of these signaling pathways permitted development of fully defined protocols that favored generation of the three GE domains. These findings provide insight into the context-dependent role of morphogens in human GE specification and are of value for in vitro disease modeling and advancement of new therapies.
起源于前脑腹侧的抑制性神经元与多种神经疾病有关。不同的前脑腹侧亚群是从前脑腹侧的特定区域产生的；外侧、内侧和尾状神经节隆起（LGE、MGE 和 CGE），然而，关键的特化因子通常跨越发育区域，导致难以确定独特的 LGE、MGE 或 CGE 特征。在这里，我们使用人类多能干细胞（hPSC）报告基因系（NKX2.1-GFP 和 MEIS2-mCherry）和形态发生梯度的操作，以更深入地了解这些不同区域的区域特化。我们发现 Sonic hedgehog (SHH)-WNT 信号通路在调节 LGE 和 MGE 命运方面存在相互作用，并揭示了视黄酸信号在 CGE 发育中的作用。揭示这些信号通路的影响允许开发完全定义的协议，有利于三个 GE 区域的生成。这些发现为形态发生素在人类 GE 特化中的上下文相关作用提供了深入的了解，对于体外疾病建模和新疗法的发展具有重要价值。
