Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development

Development. 2020 Mar 30;147(6):dev185199. doi: 10.1242/dev.185199.

Ning-Ning Song ¹, Pengcheng Ma ², Qiong Zhang ¹, Lei Zhang ³, Huishan Wang ² ⁴, Longlong Zhang ² ⁴, Liang Zhu ² ⁴, Chun-Hui He ³, Bingyu Mao ⁵ ⁶, Yu-Qiang Ding ⁷ ³

Affiliations

1 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
2 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
3 Key Laboratory of Arrhythmias, Ministry of Education of China, East Hospital, and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China.
4 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650203, China.
5 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China dingyuqiang@vip.163.com mao@mail.kiz.ac.cn.
6 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
7 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China dingyuqiang@vip.163.com mao@mail.kiz.ac.cn.

PMID: 32094113 DOI: 10.1242/dev.185199

Abstract

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.

Keywords

Locus coeruleus; Monoubiquitylation; Mouse; Noradrenergic neurons; Phox2a; Phox2b; Rnf220; Zc4h2.

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