RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern

Qian Li; Junchen Chen; Feng Liang; Jinyu Zhang; Wenzheng Qu; Xiaoli Huang; Xuejun Cheng; Xingsen Zhao; Zhanjun Yang; Shunliang Xu; Xuekun Li

doi:10.1016/j.stemcr.2021.10.013

RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern

Stem Cell Reports. 2021 Dec 14;16(12):2988-3004. doi: 10.1016/j.stemcr.2021.10.013. Epub 2021 Nov 18.

Authors

Qian Li¹, Junchen Chen¹, Feng Liang², Jinyu Zhang¹, Wenzheng Qu³, Xiaoli Huang³, Xuejun Cheng³, Xingsen Zhao¹, Zhanjun Yang⁴, Shunliang Xu⁵, Xuekun Li⁶

Affiliations

¹ 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.
² The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China.
³ The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China.
⁴ Department of Human Anatomy, Baotou Medical College, Baotou, 014040, China.
⁵ Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China. Electronic address: [email protected].
⁶ 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; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China. Electronic address: [email protected].

Abstract

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.

Keywords: CIR1; Notch; PRC1; RBPJ; Rybp; embryonic neural stem cells; neurogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors
Brain / embryology
Cell Differentiation
Cell Proliferation
Cell Shape
Embryo, Mammalian / metabolism*
Female
Mice
Mice, Inbred C57BL
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Neurogenesis*
Neurons / cytology
Neurons / metabolism
Polycomb Repressive Complex 1 / metabolism*
Receptors, Notch / metabolism*
Repressor Proteins / deficiency
Repressor Proteins / metabolism*
Signal Transduction*
Transcriptome / genetics

Substances

Basic Helix-Loop-Helix Transcription Factors
Hes5 protein, mouse
Receptors, Notch
Repressor Proteins
Rybp protein, mouse
Polycomb Repressive Complex 1