Braccioli Luca, van den Brand Teun, Alonso Saiz Noemi, Fountas Charis, Celie Patrick H N, Kazokaitė-Adomaitienė Justina, de Wit Elzo
Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
Dev Cell. 2025 Jul 21;60(14):2007-2022.e7. doi: 10.1016/j.devcel.2025.02.013. Epub 2025 Mar 17.
Correct gene expression levels are crucial for normal development. Advances in genomics enable the inference of gene regulatory programs active during development but cannot capture the complex multicellular interactions occurring during mammalian embryogenesis in utero. In vitro models of mammalian development, like gastruloids, can overcome this limitation. Using time-resolved single-cell chromatin accessibility analysis, we delineated the regulatory profile during mouse gastruloid development, identifying critical drivers of developmental transitions. Gastruloids develop from bipotent progenitor cells driven by the transcription factors (TFs) OCT4, SOX2, and TBXT, differentiating into the mesoderm (characterized by the mesogenin 1 [MSGN1]) and spinal cord (characterized by CDX2). ΔCDX gastruloids fail to form spinal cord, while Msgn1 ablation inhibits paraxial mesoderm and spinal cord development. Chimeric gastruloids with ΔMSGN1 and wild-type cells formed both tissues, indicating that inter-tissue communication is necessary for spinal cord formation. Our work has important implications for studying inter-tissue communication and gene regulatory programs in development.
正确的基因表达水平对于正常发育至关重要。基因组学的进展使得推断发育过程中活跃的基因调控程序成为可能，但无法捕捉子宫内哺乳动物胚胎发生过程中发生的复杂多细胞相互作用。哺乳动物发育的体外模型，如类原肠胚，可以克服这一限制。通过时间分辨单细胞染色质可及性分析，我们描绘了小鼠类原肠胚发育过程中的调控图谱，确定了发育转变的关键驱动因素。类原肠胚由转录因子（TFs）OCT4、SOX2和TBXT驱动的双能祖细胞发育而来，分化为中胚层（以中胚层素1 [MSGN1]为特征）和脊髓（以CDX2为特征）。ΔCDX类原肠胚无法形成脊髓，而Msgn1基因敲除则抑制了近轴中胚层和脊髓的发育。具有ΔMSGN1和野生型细胞的嵌合类原肠胚形成了这两种组织，表明组织间通讯对于脊髓形成是必要的。我们的工作对于研究发育过程中的组织间通讯和基因调控程序具有重要意义。
