mRNA-decapping associated DcpS enzyme controls critical steps of neuronal development

Homozygous mutations in the gene encoding the scavenger mRNA-decapping enzyme, DcpS, have been shown to underlie developmental delay and intellectual disability. Intellectual disability is associated with both abnormal neocortical development and mRNA metabolism. However, the role of DcpS and its scavenger decapping activity in proper neuronal development is unknown. Here, we show that differentiation of human induced pluripotent stem cell derived neurons, from patients with a DcpS mutation, are impaired and have compromised neurite outgrowth. Moreover, misexpression of DcpS in developing mouse neocortex revealed that DcpS is required for the multipolar morphology acquisition, neurite outgrowth and identity of developing neocortical glutamatergic neurons in the mouse brain. Collectively, these findings demonstrate the scavenger mRNA decapping activity contributes to multiple pivotal roles in neurodevelopment, and further corroborate that mRNA metabolism and neocortical pathologies are associated with intellectual disability. Overall design: Unbiased RNA sequencing was performed on primary neuronal cell cultures from E13 wild-type (WT) mice neocortices transfected with Ctrl shRNA (n=2) or DcpS shRNA (n=2) to identify novel downstream targets of DcpS.