The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China.
The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China.
Stem Cell Reports. 2021 Dec 14;16(12):2988-3004. doi: 10.1016/j.stemcr.2021.10.013. Epub 2021 Nov 18.
RYBP (Ring1 and YY1 binding protein), an essential component of the Polycomb repressive complex 1 (PRC1), plays pivotal roles in development and diseases. However, the roles of Rybp in neuronal development remains completely unknown. In the present study, we have shown that the depletion of Rybp inhibits proliferation and promotes neuronal differentiation of embryonic neural progenitor cells (eNPCs). In addition, Rybp deficiency impairs the morphological development of neurons. Mechanistically, Rybp deficiency does not affect the global level of ubiquitination of H2A, but it inhibits Notch signaling pathway in eNPCs. The direct interaction between RYBP and CIR1 facilitates the binding of RBPJ to Notch intracellular domain (NICD) and consequently activated Notch signaling. Rybp loss promotes CIR1 competing with RBPJ to bind with NICD, and inhibits Notch signaling. Furthermore, ectopic Hes5, Notch signaling downstream target, rescues Rybp-deficiency-induced deficits. Collectively, our findings show that RYBP regulates embryonic neurogenesis and neuronal development through modulating Notch signaling in a PRC1-independent manner.
RYBP（Ring1 和 YY1 结合蛋白）是多梳抑制复合物 1（PRC1）的一个必需组成部分，在发育和疾病中发挥关键作用。然而，RYBP 在神经元发育中的作用尚完全不清楚。在本研究中，我们表明 Rybp 的耗竭抑制胚胎神经祖细胞（eNPCs）的增殖并促进其神经元分化。此外，RYBP 缺乏会损害神经元的形态发育。在机制上，RYBP 缺乏并不影响 H2A 的泛素化的整体水平，但它抑制了 eNPCs 中的 Notch 信号通路。RYBP 和 CIR1 之间的直接相互作用促进了 RBPJ 与 Notch 细胞内结构域（NICD）的结合，从而激活了 Notch 信号通路。RYBP 的缺失促进了 CIR1 与 RBPJ 竞争与 NICD 结合，并抑制了 Notch 信号通路。此外，外源性 Hes5（Notch 信号下游靶标）挽救了 Rybp 缺失引起的缺陷。总之，我们的研究结果表明，RYBP 通过独立于 PRC1 的方式调节 Notch 信号来调节胚胎神经发生和神经元发育。
