Post-doctoral Position: Species-specific Mechanisms of ADAT Dysfunction in Cortical Development

IGBMC - Institute of Genetics and Molecular and Cellular Biology

Strasbourg, France

€ 2,940 per month gross

The recruited fellow will join the SpeaDAT project, funded by the French National Research Agency (ANR), on species-specific mechanisms of ADAT dysfunction in brain development, led by Dr. Efil Bayam (CRCN Inserm) within Dr. Juliette Godin's team “Physiological and Pathological Mechanisms of Cortical Development” at IGBMC. The Godin lab is recognized for its expertise in translational control during cortical development.

Chemical modifications on different types of RNA species have emerged as critical posttranscriptional modulators of brain development and function. While transfer RNAs (tRNA) are required for translation in all cells, 77% of the pathogenic mutations in transfer RNA (tRNA) modification enzymes manifest as neurodevelopmental disorders (NDDs) suggesting that developing human brain is particularly sensitive to disrupted tRNA modifications. Recently, the team identified the NDD-associated ADAT complex (ADAT2/3), which catalyzes the conversion of Adenine (A) to Inosine (I) at position 34 of 8 ANN-tRNAs, as a regulator of cortical development and showed the pathogenicity of NDD-relevant ADAT mutations.

Surprisingly, despite the profound impact of ADAT dysfunction in humans, mouse genetic models mimicking the ADAT dysfunction displayed no detectable brain phenotype or tRNA alterations suggesting species-specific vulnerability to defects in ADAT complex.

The postdoctoral researcher will investigate species-specific ADAT functions in progenitors and neurons, and characterize the impact of ADAT dysfunction on tRNAs and translational programs, using human iPSC- and mouse ESC- derived models, including 2D cortical neural stem cells/neurons and 3D cortical organoids carrying ADAT2/ADAT3 pathogenic variants.

Activities

• Generate and characterize human iPSC and mouse ESC-derived 2D cortical neural stem cells, neurons and 3D cortical organoids carrying ADAT2/ADAT3 pathogenic variants;
• Assess cellular phenotypes (proliferation, cell cycle dynamics, progenitor identity, neuronal maturation, synaptic integration) using immunofluorescence, EdU/pulse-chase labeling and functional assays (MEA, calcium imaging);
• Analyze and interpret human mim-tRNA-seq and ribosome profiling data to characterize species- specific tRNA and translational programs, in close collaboration with a bioinformatician;
• Present research findings at team and consortium meetings and at national/international conferences; contribute to manuscript writing, project reporting, and the supervision of students.

Compétences techniques

• PhD in Cell Biology, Molecular Biology, Developmental Biology, Neuroscience or a related field, recently obtained. - Experience with human iPSC culture and/or 2D/3D neural differentiation protocols is required as well as proficiency in standard molecular and cell biology techniques (immunofluorescence, western blot, qPCR, imaging);
• Familiarity with high-throughput sequencing approaches (RNA-seq, ribosome profiling) is a plus;
• Interest in neurodevelopment, neurodevelopmental disorders and translational control/epitranscriptomics;
• Fast learner, autonomous, with strong organizational and communication skills (English, fluent, required), and the ability to work within an interdisciplinary, international consortium.