School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK.
Neuroscience Institute, The University of Sheffield, Sheffield S10 2TN, UK.
Development. 2024 Feb 1;151(3). doi: 10.1242/dev.202098. Epub 2024 Feb 12.
The generation of the post-cranial embryonic body relies on the coordinated production of spinal cord neurectoderm and presomitic mesoderm cells from neuromesodermal progenitors (NMPs). This process is orchestrated by pro-neural and pro-mesodermal transcription factors that are co-expressed in NMPs together with Hox genes, which are essential for axial allocation of NMP derivatives. NMPs reside in a posterior growth region, which is marked by the expression of Wnt, FGF and Notch signalling components. Although the importance of Wnt and FGF in influencing the induction and differentiation of NMPs is well established, the precise role of Notch remains unclear. Here, we show that the Wnt/FGF-driven induction of NMPs from human embryonic stem cells (hESCs) relies on Notch signalling. Using hESC-derived NMPs and chick embryo grafting, we demonstrate that Notch directs a pro-mesodermal character at the expense of neural fate. We show that Notch also contributes to activation of HOX gene expression in human NMPs, partly in a non-cell-autonomous manner. Finally, we provide evidence that Notch exerts its effects via the establishment of a negative-feedback loop with FGF signalling.
颅后胚胎体的生成依赖于神经脊外胚层和体节中胚层细胞从神经中胚层祖细胞（NMPs）的协调产生。这一过程由前神经和前中胚层转录因子协调，这些转录因子与 Hox 基因一起在 NMPs 中共同表达，Hox 基因对于 NMP 衍生物的轴向分配至关重要。NMPs 位于一个后部生长区域，该区域的特征是 Wnt、FGF 和 Notch 信号成分的表达。尽管 Wnt 和 FGF 在影响 NMP 的诱导和分化中的重要性已得到充分证实，但 Notch 的精确作用仍不清楚。在这里，我们表明 Wnt/FGF 驱动的人胚胎干细胞（hESCs）NMP 诱导依赖于 Notch 信号。通过使用 hESC 衍生的 NMP 和鸡胚移植，我们证明 Notch 以牺牲神经命运为代价指导中胚层特性。我们还表明，Notch 也有助于激活人类 NMP 中 HOX 基因的表达，部分以非细胞自主的方式。最后，我们提供的证据表明 Notch 通过与 FGF 信号建立负反馈环来发挥其作用。
