Modifying tRNAs: a key process to regulate brain development?

Dr Godin’s research interest focuses on the importance of transfer RNA (tRNA) which are critical regulators of cell homeostasis in their function in mRNA translation. In recent years, tRNAs are emerging as a key determinant of corticogenesis, since defects in tRNA expression or function are strongly connected to neuronal damage. More than 2/3 of human diseases caused by these defects are neurodevelopmental diseases.

One of the focuses of Dr Godin’s research is on the tRNA Elongator complex. Dr Godin found this complex is associated with cortex development. Another area her research is focused on is the deaminase complex (ADAT2/ADAT3), in which ADAT2 has the catalytic activity and ADAT3 is the essential partner to recognize tRNAs. ADAT is an essential complex that modifies up to eight tRNAs and catalyses the adenine into inosine conversion.

Dr Godin’s talk started with a brief introduction about cortical development and what are the similarities between humans and mice. Both organisms have 6 cortical layers and their cortical development entails 3 major steps: neurogenesis, migration, and maturation. Impairment in any of these steps leads to neurodevelopmental disorders such as human cortical malformations, often linked to intellectual disability and epilepsy. Therefore, the control of each step is important for proper cortical formation.

Dr Godin mentioned that although the genetic code is made of 61 codons, that code for the 20 amino acids, there are only 49 different anticodons in humans. This is due to the Wobble hypothesis that applies to most tRNAs.

In her work, the complex was knocked out in mice specifically in the forebrain, which resulted in microcephaly. At the cellular level, she found that there was a significant decrease in the proliferation of cortical progenitors. However, the number of apical progenitors of the ventricular zone didn’t change in the knockout mice. Intriguingly, there was a huge difference in the number of intermediate progenitors between the knockout and wild type mice. Notably, depletion of Elp3 caused a reduction in the number of immature intermediate progenitors (Pax6 and Tbr2).

Dr Godin also noticed that there is an impaired balance between indirect and direct neurogenesis. She checked for protein acetylation in the knockout mice but surprisingly did not observe any phenotype. However, thanks to mRNA sequencing she uncovered that depletion of Elp3 enhanced endoplasmic reticulum stress and unfolded protein response. This upregulated level was causing microcephaly.

In the search for what causes this upregulated unfolded protein response (UPR), Dr Godin turned to tRNA modifications. She’s shown that Elp3 depletion impairs specific modification of tRNAs that lead to increased pausing of ribosomes on specific codons. This is what was causing the protein misfolding and UPR.

Dr Godin finished the talk with the information that she has identified new variants in ADAT3 in patients with microcephaly. During her research, she has found that both neurogenesis and neuronal migration require the tRNA modification activity of the ADAT complex in mouse cortices. By using cell lines of patients with microcephaly, she has shown that both tRNA deamination and steady-state were affected in humans. This was achieved by using a newly established tRNA sequencing method in her lab.

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