Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.

Abstract

Sonic hedgehog (Shh) signaling is essential for the proliferation of cerebellar granule neuron progenitors (CGNPs), and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma (MB). During vertebrate neural development, RNF220, a ubiquitin E3 ligase, is involved in spinal cord patterning by modulating the subcellular location of glioma-associated oncogene homologs (Glis) through ubiquitination. RNF220 is also required for full activation of Shh signaling during cerebellum development in an epigenetic manner through targeting embryonic ectoderm development. ZC4H2 was reported to be involved in spinal cord patterning by acting as an RNF220 stabilizer. Here, we provided evidence to show that ZC4H2 is also required for full activation of Shh signaling in CGNP and MB progression by stabilizing RNF220. In addition, we found that the ubiquitin E3 ligase RING finger LIM domain-binding protein (RLIM) is responsible for ZC4H2 stabilization via direct ubiquitination, through which RNF220 is also thus stabilized. RLIM is a direct target of Shh signaling and is also required for full activation of Shh signaling in CGNP and MB cell proliferation. We further provided clinical evidence to show that the RLIM‒ZC4H2‒RNF220 cascade is involved in Shh-group MB progression. Disease-causative human RLIM and ZC4H2 mutations affect their interaction and regulation. Therefore, our study sheds light on the regulation of Shh signaling during cerebellar development and MB progression and provides insights into neural disorders caused by RLIM or ZC4H2 mutations.

• Authors: Yuwei Li, Chencheng Yang, Huishan Wang, Ling Zhao, Qinghua Kong, Yu Cang, Shuhua Zhao, Longbao Lv, Yan Li, Bingyu Mao, Pengcheng Ma
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 14 Issue 1 (04 05 2022) ISSN: 1759-4685 [Electronic] United States
• PMID: 35040952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.

Chemical References

• Hedgehog Proteins
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• SHH protein, human
• ZC4H2 protein, human
• RLIM protein, human
• RNF220 protein, human
• Ubiquitin-Protein Ligases

Topics

• Cerebellar Neoplasms (metabolism)
• Cerebellum
• Hedgehog Proteins (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Medulloblastoma (genetics, metabolism)
• Neurogenesis (genetics)
• Nuclear Proteins (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)