Orb2 enables rare-codon-enriched mRNA expression during Drosophila neuron differentiation

Rebeccah K. Stewart, Patrick Nguyen, Alain Laederach, Pelin C. Volkan, Jessica K. Sawyer and Donald T. Fox ()
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Rebeccah K. Stewart: Duke University
Patrick Nguyen: Duke University
Alain Laederach: University of North Carolina
Pelin C. Volkan: Duke University
Jessica K. Sawyer: Duke University
Donald T. Fox: Duke University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Regulation of codon optimality is an increasingly appreciated layer of cell- and tissue-specific protein expression control. Here, we use codon-modified reporters to show that differentiation of Drosophila neural stem cells into neurons enables protein expression from rare-codon-enriched genes. From a candidate screen, we identify the cytoplasmic polyadenylation element binding (CPEB) protein Orb2 as a positive regulator of rare-codon-dependent mRNA stability in neurons. Using RNA sequencing, we reveal that Orb2-upregulated mRNAs in the brain with abundant Orb2 binding sites have a rare-codon bias. From these Orb2-regulated mRNAs, we demonstrate that rare-codon enrichment is important for mRNA stability and social behavior function of the metabotropic glutamate receptor (mGluR). Our findings reveal a molecular mechanism by which neural stem cell differentiation shifts genetic code regulation to enable critical mRNA stability and protein expression.

Date: 2024
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DOI: 10.1038/s41467-024-48344-8

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