视网膜母细胞瘤家族蛋白（RBs）和E2F转录因子是细胞自主调控细胞周期进程的调节因子，但它们除了抑制肿瘤生长外，也影响了细胞命运选择。涉及的机制范围有待揭示。在这里，我们展示了RBs，尤其是RBL2/p130，通过抑制WNT4和WNT8A等WNT配体，在神经嵴和神经上皮之间定向外胚层的特化。RBL2通过与E2Fs和GCN5在WNT基因调控区域上的细胞周期依赖性协作来实现这一功能，通过WNT/β-连环蛋白和DLL/NOTCH信号活性的时间波动来指导神经上皮确定和神经嵴确定。因此，RB-E2F的细胞周期自主轴控制细胞命运决策，RBL2通过WNT配体调节领域效应。这揭示了RBL2-E2F在干细胞和组织前体分化中的非细胞周期自主功能，对器官发生、成体干细胞、组织稳态和肿瘤发生具有更广泛的意义。 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

The retinoblastoma family proteins (RBs) and E2F transcription factors are cell-autonomous regulators of cell-cycle progression, but they also impact fate choice in addition to tumor suppression. The range of mechanisms involved remains to be uncovered. Here, we show that RBs, particularly RBL2/p130, repress WNT ligands such as WNT4 and WNT8A, thereby directing ectoderm specification between neural crest to neuroepithelium. RBL2 achieves this function through cell-cycle-dependent cooperation with E2Fs and GCN5 on the regulatory regions of WNT loci, which direct neuroepithelial versus neural crest specification by temporal fluctuations of WNT/β-catenin and DLL/NOTCH signaling activity. Thus, the RB-E2F bona fide cell-autonomous axis controls cell fate decisions, and RBL2 regulates field effects via WNT ligands. This reveals a non-cell-autonomous function of RBL2-E2F in stem cell and tissue progenitor differentiation that has broader implications for cell-cycle-dependent cell fate specification in organogenesis, adult stem cells, tissue homeostasis, and tumorigenesis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.