Tran Luuli N, Shinde Ashwini, Schuster Kristen H, Sabaawy Aiman, Dale Emily, Welch Madalynn J, Isner Trevor J, Nunez Sylvia A, García-Moreno Fernando, Sagerström Charles G, Appel Bruce H, Franco Santos J
Molecular Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
bioRxiv. 2025 Jan 21:2025.01.20.633996. doi: 10.1101/2025.01.20.633996.
The remarkable cell diversity of multicellular organisms relies on the ability of multipotent progenitor cells to generate distinct cell types at the right times and locations during embryogenesis. A key question is how progenitors establish competence to respond to the different environmental signals required to produce specific cell types at critical developmental timepoints. We addressed this in the mouse developing forebrain, where neural progenitor cells must switch from producing neurons to making oligodendrocytes in response to increased Sonic Hedgehog (SHH) signaling during late embryogenesis. We show that progenitor responses to SHH are regulated by Notch signaling, thus permitting proper timing of the neuron-oligodendrocyte switch. Notch activity epigenetically primes genes associated with the oligodendrocyte lineage and SHH pathway, enabling amplified transcriptional responses to endogenous SHH and robust oligodendrogenesis. These results reveal a critical role for Notch in facilitating progenitor competence states and influencing cell fate transitions at the epigenetic level.
多细胞生物显著的细胞多样性依赖于多能祖细胞在胚胎发生过程中于正确的时间和位置产生不同细胞类型的能力。一个关键问题是祖细胞如何建立能力，以响应在关键发育时间点产生特定细胞类型所需的不同环境信号。我们在小鼠发育中的前脑解决了这个问题，在那里神经祖细胞必须在胚胎后期响应增加的音猬因子（SHH）信号，从产生神经元转变为生成少突胶质细胞。我们表明，祖细胞对SHH的反应受Notch信号调节，从而允许神经元 - 少突胶质细胞转换的正确时间安排。Notch活性在表观遗传上使与少突胶质细胞谱系和SHH途径相关的基因致敏，从而能够对内源性SHH产生放大的转录反应并实现强大的少突胶质细胞生成。这些结果揭示了Notch在促进祖细胞能力状态和在表观遗传水平影响细胞命运转变中的关键作用。
