Journal
DEVELOPMENT
Volume 147, Issue 6, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.185199
Keywords
Rnf220; Zc4h2; Noradrenergic neurons; Locus coeruleus; Phox2a; Phox2b; Monoubiquitylation; Mouse
Categories
Funding
- Science and Technology Commission of Shanghai Municipality Major Project [2018SHZDZX01]
- ZJLab, 'Strategic Priority Research Program' of the Chinese Academy of Sciences [XDB13000000]
- National Natural Science Foundation of China [31671061, 81571332, 31771134, 31671521, 31871483, 31500847]
- National Key R&D Program of China (Ministry of Science and Technology of China) [2017YFA0104002]
- Applied Basic Research Foundation of Yunnan Province [2016FB043]
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Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2. In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.
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