mRNA Stability Fine-tunes Gene Expression in the Developing Cortex to Control Neurogenesis
Lucas D. Serdar, Jacob R. Egol, Brad Lackford, Brian D. Bennett, Guang Hu, Debra L. Silver
Abstract
RNA abundance is controlled by rates of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we discover the landscape of RNA stability regulation in the cerebral cortex and demonstrate that intact RNA decay machinery is essential for corticogenesis in vivo.
Introduction
The cerebral cortex is essential for higher order functions, including cognitive reasoning, and somatosensory, motor, and visual processing. These processes rely on proper embryonic development, and defective embryonic corticogenesis can lead to neurodevelopmental disorders, including autism, schizophrenia, and intellectual disability. The developmental trajectory and underlying biological and molecular events necessary to construct the cortex during development are generally well defined.
Materials and Methods:
Sequenced reads were processed with the SlamDunk tool v0.4.3, using the mm10 genome and exons extracted from the GENCODE vM24 gene annotation. The number of covered (T)s and converted (T)s for each exon was extracted from the SlamDunk results. Covered (T) counts for all exons within a gene were summed together, and the same was done for converted (T)s. A conversion rate was calculated for each gene as the percentage of converted (T)s to covered (T)s.
Discussion:
RNA regulation in the developing cortex is dynamic, with rapid changes in expression across dual axes of time and differentiation. RNA expression levels are determined by complementary rates of synthesis and degradation, but the quantitative contribution of the latter to cortical development is largely unknown. We apply omics analyses and genetic approaches to define how RNA turnover controls cortical development.
Acknowledgments:
We thank members of the Silver and Hu labs for helpful discussions and careful reading of the manuscript.
Citation: Serdar LD, Egol JR, Lackford B, Bennett BD, Hu G, Silver DL (2025) mRNA stability fine-tunes gene expression in the developing cortex to control neurogenesis. PLoS Biol 23(2): e3003031. https://doi.org/10.1371/journal.pbio.3003031
Editor: Bassem A. Hassan, ICM, FRANCE
Received: August 10, 2024; Accepted: January 23, 2025; Published: February 6, 2025.
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: Sequencing data has been deposited and made publicly available on GEO under accession numbers GSE281690 (RNA-seq) and GSE281693 (SLAM-seq).
Funding: This work was supported by the Extramural and Intramural Research Programs of the National Institutes of Health: F32HD107972 to L.D.S., R01NS083897, R01NS120667, R37NS110388, R01MH132089, R21NS128374 to D.L.S., and Z01ES102745 to G.H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
