Institut Jacques Monod, CNRS UMR7592, Université Paris Diderot, Sorbonne Paris Cité, 75205 Paris Cedex, France.
Institut Pasteur, Department of Developmental and Stem Cell Biology, CNRS URA 2578, 75015 Paris, France.
Development. 2019 Jul 25;146(14):dev175430. doi: 10.1242/dev.175430.
Bone morphogenetic proteins (BMPs) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity , whether this is sufficient for pattern formation is unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cell-derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types, and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species-specific tempo of neural differentiation. Together, this study describes efficient methods for generating patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.
骨形态发生蛋白（BMPs）是几种发育组织中细胞命运的分泌调节剂。在胚胎脊髓中，它们控制神经嵴、基板和背侧中间神经元的不同亚群的出现。尽管已经提出 BMP 活性梯度来决定细胞类型的身份，但这是否足以形成模式尚不清楚。在这里，我们证明 BMP4 的暴露会在小鼠和人多能干细胞衍生的脊髓类器官的自我出现的上皮内引发 BMP 信号的不同空间动态。BMP 信号的模式导致背侧神经管细胞类型的刻板空间排列，并且 BMP4 暴露的浓度、时间和持续时间调节这些模式。此外，小鼠和人之间的能力时间窗持续时间的差异解释了神经分化的种特异性节奏。总之，这项研究描述了在脊髓类器官中生成背侧中间神经元模式亚群的有效方法，并支持这样的结论，即分级 BMP 活性协调了小鼠和人背侧神经管细胞多样性的空间组织。
