The H3K27 Demethylase JMJD3 Is Required for Maintenance of the Embryonic Respiratory Neuronal Network, Neonatal Breathing, and Survival

JMJD3 (KDM6B) antagonizes Polycomb silencing by demethylating lysine 27 on histone H3. The interplay of methyltransferases and demethylases at this residue is thought to underlie critical cell fate transitions, and the dynamics of H3K27me3 during neurogenesis posited for JMJD3 a critical role in the acquisition of neural fate. Despite evidence of its involvement in early neural commitment, however, its role in the emergence and maturation of the mammalian CNS remains unknown. Here, we inactivated Jmjd3 in the mouse and found that its loss causes perinatal lethality with the complete and selective disruption of the pre-Bötzinger complex (PBC), the pacemaker of the respiratory rhythm generator. Through genetic and electrophysiological approaches, we show that the enzymatic activity of JMJD3 is selectively required for the maintenance of the PBC and controls critical regulators of PBC activity, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks. [Display omitted] ► JMJD3 inactivation in mouse causes perinatal lethality through respiratory failure ► JMJD3 is necessary for the maintenance of the respiratory pacemaker pre-Bötzinger complex (PBC) ► PBC maintenance and function require the enzymatic activity of JMJD3 ► JMJD3 controls key PBC-specific genes through histone H3 lysine 27 demethylation JMJD3 (KDM6B) antagonizes Polycomb silencing through demethylation of lysine 27 on histone H3. Testa and colleagues inactivated it in the mouse and found that its loss causes perinatal lethality through complete failure of the respiratory pacemaker pre-Bötzinger complex (PBC). The enzymatic activity of JMJD3 was required to maintain PBC function in late embryogenesis and to activate several PBC-specific genes, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks.