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The E3 ubiquitin ligase RNF220 maintains hindbrain Hox expression patterns through regulation of WDR5 stability.

Huishan Wang | Xingyan Liu | Yamin Liu | Chencheng Yang | Yaxin Ye | Xiaomei Yu | Nengyin Sheng | Shihua Zhang | Bingyu Mao | Pengcheng Ma
eLife | 2024

The spatial and temporal linear expression of Hox genes establishes a regional Hox code, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural development via targeting of multiple substrates. Here, we found that the expression of Hox genes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.5) in Rnf220-/- and Rnf220+/- mouse embryos. Single-nucleus RNA sequencing (RNA-seq) analysis revealed different Hox de-repression profiles in different groups of neurons, including the pontine nuclei (PN). The Hox pattern was disrupted and the neural circuits were affected in the PN of Rnf220+/- mice. We showed that this phenomenon was mediated by WDR5, a key component of the TrxG complex, which can be polyubiquitinated and degraded by RNF220. Intrauterine injection of WDR5 inhibitor (WDR5-IN-4) and genetic ablation of Wdr5 in Rnf220+/- mice largely recovered the de-repressed Hox expression pattern in the hindbrain. In P19 embryonal carcinoma cells, the retinoic acid-induced Hox expression was further stimulated by Rnf220 knockdown, which can also be rescued by Wdr5 knockdown. In short, our data suggest a new role of RNF220/WDR5 in Hox pattern maintenance and pons development in mice.

Pubmed ID: 39526890

Associated grants

  • Agency: National Key R&D Program of China,
    Id: 2021YFF0702700
  • Agency: Yunnan Fundamental Research Projects,
    Id: 202101AU070137
  • Agency: National Natural Science Foundation of China,
    Id: 8240055266
  • Agency: National Natural Science Foundation of China,
    Id: 32170965
  • Agency: Yunnan Fundamental Research Projects,
    Id: 202205AC160065
  • Agency: Yunnan Fundamental Research Projects,
    Id: 202201AW070009
  • Agency: Yunnan Fundamental Research Projects,
    Id: 202301AS070059
  • Agency: Yunnan Fundamental Research Projects,
    Id: 202401AT070187

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Chinese Genome Sequence Archive (tool)

RRID:SCR_025826

Public archive of raw sequence data in National Genomics Data Center as part of the China National Center for Bioinformation. GSA accepts worldwide data submissions, performs data curation and quality control for all submitted data. Provides data storage and sharing services.

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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Anti-CBX6 Antibody (H-1) (antibody)

RRID:AB_2923357

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EZH2 antibody (antibody)

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MPc3 (C-3) (antibody)

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WDR5 (D9E1I) Rabbit mAb (antibody)

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This unknown targets WDR5

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Alpha Tubulin antibody (antibody)

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CBX7 (G-3) (antibody)

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RYBP (A-1) (antibody)

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goat anti-rabbit IgG-AP (antibody)

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RNF2-human (antibody)

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