Rnf220 cooperates with Zc4h2 to specify spinal progenitor domains [RESEARCH ARTICLE]

Jumee Kim, Tae-Ik Choi, Shinhye Park, Myung Hee Kim, Cheol-Hee Kim, and Seunghee Lee

During early embryonic development of the spinal cord, graded sonic hedgehog signaling establishes distinct ventral progenitor domains by regulating the spatiotemporal expression of fate-specifying transcription factors. However, regulation of their protein stability remains incompletely understood. Here, we show that RNF220, an E3 ubiquitin ligase, plays crucial roles in the generation of the ventral progenitor domains, which produce ventral interneurons and motor neurons, by targeting key transcription factors including Dbx1/2 and Nkx2.2 for degradation. Surprisingly, RNF220 interacts with, and is co-expressed with, a zinc-finger protein ZC4H2, and they cooperate to degrade Dbx1/2 and Nkx2.2. RNF220-null mice show widespread alterations of ventral progenitor domains, including the loss of the p2 domain that produces V2 interneurons. Knockdown of RNF220 and ZC4H2 in the chick spinal cord downregulates expression of the V2 interneuronal marker Chx10. Co-expression of RNF220 and ZC4H2 further promotes the ability of Nkx6.1 to induce ectopic Chx10⁺ V2 interneurons. Our results uncover a novel regulatory pathway in establishing distinct progenitor domains through modulating the protein stability of transcription factors. Our results provide insights into the molecular mechanism by which ZC4H2 mutations lead to human syndromes characterized by delayed motor development.

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