Translational control of corticogenesis

• Applicant: Professorin Dr. Danny Nedialkova
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431372074

Cortical development progresses through several stages, including neural proliferation, migration and differentiation. Disrupting the completion of one of these steps often leads to brain abnormalities. Characterizing the molecular controls driving the maturation of cortical progenitors into neurons is fundamental to understand how cortical functions emerge during development. While hierarchy and lineage relationships existing among cortical progenitors are emerging, the molecular mechanisms controlling progenitor transition and their progressive specification toward the neuronal lineage in the cortex remain poorly understood.The cellular pool of transfer RNA (tRNA) is emerging as an unexpected key determinant of successful corticogenesis. Transfer RNAs are critical regulators of cell homeostasis in their role of adaptors in mRNA translation. By dictating the efficiency and accuracy of translation, cellular tRNA abundance controls proteome quantity and quality. As proteomes are as diverse as the cell types, tRNA repertoires need to extensively vary in distinct cell types. The mammalian brain expresses high levels of tRNAs compared to many other tissues, and exhibits high variability in the tRNA pool between embryonic and adult stages. Accordingly, defects in tRNA expression or function are strongly linked to neuronal damage. Notably, 79% of human diseases linked to genes involved in cytoplasmic tRNA expression, maturation or function are neurological disorders, with a particular enrichment in neurodevelopmental conditions. The first insights into the molecular mechanisms underlying the role of tRNAs in neurodevelopmental processes come from our prior work, in which we showed that aberrant tRNA modification in cortical progenitors impairs translation speed at specific codons. This defect triggers ER stress, leading to premature neuron generation and microcephaly in mice. Taken together, these initial findings suggest a particular vulnerability of the human brain to cytoplasmic tRNA impairment, raising the intriguing possibility of tRNA-mediated regulatory pathways in the developing brain. Which tRNA-driven molecular pathways contribute to corticogenesis remains unknown, and how tRNA pools are regulated in the developing brain under physiological and pathological conditions has not been explored. To address this knowledge gap, this project will define how tRNA pools are shaped and how they dictate specific translational programs during cortical development to enable the generation of neurons. Using genome-wide assays and cortical embryonic neurogenesis in the mouse as a model system, we will address these questions by 1) creating a high-resolution map of tRNA repertoires at key developmental stages; 2) identifying translational programs that drive key neurodevelopmental processes (i.e. proliferation, migration) and are dictated by cellular tRNA content; and 3) determining the physiological impact of tRNA perturbations during cortical development

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Juliette Godin, Ph.D.