Speaker
Description
With the identification of ~150 modifications found in RNA, epitranscriptomic modifications emerged as critical posttranscriptional modulators of brain development and function. tRNAs, the adaptor molecules that deliver specific amino acids to the polypeptide chain during translation, are the most modified RNA species, with an average of 13 modifications per tRNA. These modifications, catalyzed by over 70 different tRNA modifying enzymes, influence tRNA structure, stability and function depending on their chemical nature and position on the tRNA. Strikingly, while more than half of these modifications is linked to human diseases, most of the diseases linked to mutations in genes encoding for tRNA-modifying enzymes are NDDs suggesting a clear vulnerability of the developing human brain to disturbances of tRNA modifications. One such tRNA modification introduced by the ADAT2/3 complex, the conversion of Adenine (A) to Inosine (I) at position 34 (I34) in ANN-tRNAs, extends the base-pairing capacity of tRNA’s as -I can base pair with -U, - A and -C and is essential for decoding the C-ending codons encoding the 8 amino acids, as GNN-tRNAs do not exist in eukaryote genomes. While mutations in ADAT3, the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs) the biological role of the ADAT complex during cortical development and the effect of NDD related ADAT3 mutations remains uncharacterized.
Here we show that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. Through structural, biochemical and molecular analysis, we demonstrated that all the identified variants alter both the abundance and the activity of the complex leading to a significant decrease of I 34 with direct consequence on the steady-state levels of ADAT target tRNAs. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.
| Author(s) | Efil Bayam*(1,2,3,4),Jordi Del-Pozo-Rodriguez(1,2,3,4), Peggy Tilly(1,2,3,4), Romain Lecat(1,2,3,4), Hugo Rolando Vaca(1,2,3,4), Laureline Mosser(5), Elena Brivio(1,2,3,4),Juliette D Godin(1,2,3,4) |
|---|---|
| Affiliation(s) | "1. IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, F-67400 Illkirch, France. 2. CNRS, Centre National de la Recherche Scientifique, UMR 7104, F-67400 Illkirch, France. 3. INSERM, Institut National de la Santé et de la Recherche Médicale, UMR-S 1258, F-67400 Illkirch, France. 4. Université de Strasbourg, IGBMC UMR 7104- UMR-S 1258, F-67400 Illkirch, France. 5. Institut de biologie moléculaire des plantes, CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084 Strasbourg, France" |
