RNF220/ZC4H2-mediated monoubiquitination of Phox2 is required for noradrenergic neuron development

Abstract

Noradrenaline belongs to monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play critical but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in 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 through the mechanisms remain poorly understood. Here, we report that ZC4H2 and RNF220 are required for the development of central NA neurons in mouse brain. Both ZC4H2 and RNF220 are expressed in developing LC-NA neurons. Although properly initiated at embryonic day (E) 10.5, the expression of genes associated with LC-NA neurons are not maintained at the later embryonic stages in mice with deficiency of either RNF220 or ZC4H2. In addition, we show that the RNF220/ZC4H2 complex monoubiquitinates Phox2a/Phox2b, which is 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.