Mecp2 regulates<i>tnfa</i>during zebrafish embryonic development and acute inflammation

Abstract

Mutations in <i>MECP2</i> cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of <i>MECP2</i> also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MECP2 in controlling immune and inflammatory responses. Here, we used <i>mecp2</i>-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2 deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. By contrast, expression of the proinflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in <i>mecp2</i>-null animals during development, representing the earliest developmental phenotype described for MECP2 deficiency to date. Expression of <i>tnfa</i> was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional <i>mecp2</i> Thus, Mecp2 is required for <i>tnfa</i> expression during zebrafish development and inflammation. Finally, RNA sequencing of <i>mecp2</i>-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes.