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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE173603 | GEO | 2022/04/06

REPOSITORIES: GEO

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Project description:Mass spectrometry peptidomics coupled with RNA deep sequencing has revealed a large number of translated eukaryotic short open reading frames that produce genomically encoded peptides. The human LOC550643 gene, previously annotated as non-coding, encodes such a peptide (referred to as NoBody). NoBody peptide binds to EDC4 (enhancer of decapping 4) site-specifically, enriches complexes of proteins involved in 5'-3' mRNA degradation, and localizes to P-bodies, which are cellular RNA-protein granules associated with RNA degradation. Furthermore, modulating NoBody expression levels inversely regulates P-body numbers. This peptide has the potential to reveal new insights into the P-body structure-function relationship and cellular regulation of mRNA degradation. We used siRNA-mediated gene silencing coupled with biological pathway analysis to determine the cellular functions of NoBody (LOC550643), and whether it has similar cellular functions to related (Dcp2) and unrelated (DcpS) mRNA degradation proteins. HEK293T cells were silenced for NoBody/LOC550643 expression by transfection with a pool of 4 commercially designed siRNAs (Qiagen). The negative control/reference sample consisted of HEK293T cells transfected with a non-targeting siRNA. Comparison samples were silenced for Dcp2 expression (expected to be functionally related in mRNA decapping and degradation, positive control), DcpS (another mRNA degradation protein from a different pathway, expected to be unrelated, negative control) or GAPDH (unrelated protein, negative control), so that the specificity of cellular responses to NoBody/LOC550643 silencing could be assessed. 48 hours after transfection with siRNA, cells were treated with actinomycin D for 4 hours (expected to blunt transcriptional responses to assay mRNA degradation phenotypes), then harvested and total RNA was extracted and subjected to Affymetrix GeneChip analysis. We note that the mRNA degradation phenotype was apparently overwhelmed by transcriptional responses despite the actinomycin D treatment, so the most meaningful analyses of the data involved gene ontology/biological pathway analysis.

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

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