Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence

Abstract

Summary: To determine the role for mutations of MECP2 in Rett syndrome, we generated isogenic lines of human induced pluripotent stem cells, neural progenitor cells, and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal-specific gene expression changes, including induction of a senescence-associated secretory phenotype (SASP) program. Patient-derived neurons made without MECP2 showed signs of stress, including induction of P53, and senescence. The induction of P53 appeared to affect dendritic branching in Rett neurons, as P53 inhibition restored dendritic complexity. The induction of P53 targets was also detectable in analyses of human Rett patient brain, suggesting that this disease-in-a-dish model can provide relevant insights into the human disorder. : In this report, Lowry and colleagues found that loss of MECP2 has a more profound effect as pluripotent stem cells are terminally differentiated toward neurons. The loss of MECP2 leads to induction of P53 protein and subsequent senescence pathways including an SASP gene program, which appears to be a cause of diminished dendritic branching in Rett neurons. Keywords: MECP2, Rett syndrome, disease in a dish, senescence