DC 9: General and mRNA-specific translation downstream of mTOR in human neurodevelopment

Project part of Work Package 2

Objectives: One of the best ascribed functions of mTOR is regulation of protein synthesis, also termed translational control. mTOR exerts tight control on gene expression at the level of general translation, but also mRNA-specific translation by preferentially stimulating or inhibiting the synthesis of specific subsets of proteins. While mTOR-sensitive mRNAs have been identified in mature brain using mouse models, this analysis has not been performed during early development. Moreover, little is known about the role of mTOR in regulating protein synthesis in early human brain development. Human induced pluripotent stem cell-derived brain organoids have emerged as a powerful model to study early development, as they recapitulate >96% of human embryonic brain gene expression and cytoarchitecture to a large extent. To elucidate the role of mTOR in translational control during early human brain development, the doctoral candidate will use translational profiling to assess general (metabolic labelling) and mRNA-specific (ribosome profiling) in human brain organoids where mTOR is upregulated and downregulated genetically or pharmacologically. We will further use structural and sequence analysis for mTOR-sensitive mRNAs to identify common molecular features. Understanding mTOR-regulated mechanisms of translational control in early human brain development will also contribute to elucidate the pathophysiology of neurodevelopmental mTORopathies, such as autism spectrum disorder.

Expected Results: Identify changes in general and mRNA-specific translation in human iPSC-derived brain organoids. Reveal structural features of mRNAs preferentially translated by mTOR and elucidate mechanisms of translational control in the human brain during early development. Modulate translation and organoid morphogenesis by manipulating these candidate genes and by testing selected compounds.

Prospects of career development: BRI-FORTH has a strong track record of training highly qualified doctoral researchers who subsequently secure positions in academia, industry, and clinical settings. The successful candidate will develop a broad skill set including expertise in stem cell biology, transcriptomics, neurodevelopment, and translational control, as well as complementary skills such as scientific communication, project management, and grant writing. Networking opportunities through local and international collaborations, as well as exposure to cutting-edge technologies, will facilitate a smooth transition to the next stage of the candidate’s career. Graduates of BRI-FORTH have pursued successful paths as principal investigators in academia, research scientists in pharmaceutical and biotech industries, and leaders in science policy and administration, reflecting the Institute’s strong reputation and extensive professional network.

Planned secondments: 3 months at Institut du Cerveau/Paris Brain Institutefor evaluating the involvement of new alleles in autistic spectra. 3 months at Topadur for testing the activity of putative mTOR inhibitors in organoids