RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis.

Haploinsufficient mutation in arginine and glutamine-rich protein 1 (Arglu1), a newly identified pre-mRNA splicing regulator, may be linked to neural developmental disorders associated with mental retardation and epilepsy in human patients, but the underlying causes remain elusive. Here we show that ablation of Arglu1 promotes radial glial cell (RG) detachment from the ventricular zone (VZ), leading to ectopic localized RGs in the mouse embryonic cortex. Although they remain proliferative, ectopic progenitors, as well as progenitors in the VZ, exhibit prolonged mitosis, p53 upregulation and cell apoptosis, leading to reduced neuron production, neuronal loss and microcephaly. RNA seq analysis reveals widespread changes in alternative splicing in the mutant mouse embryonic cortex, preferentially affecting genes involved in neuronal functions. Mdm2 and Mdm4 are found to be alternatively spliced at the exon 3 and exon 5 respectively, leading to absence of the p53-binding domain and nonsense-mediated mRNA decay (NMD) and thus relieve inhibition of p53. Removal of p53 largely rescues the microcephaly caused by deletion of Arglu1. Our findings provide mechanistic insights into cortical malformations of human patients with Arglu1 haploinsufficient mutation.