The role of cellular stress-associated protein Ire1α in the development of the cerebral cortex.
Final Report Abstract
The proposed project aimed to investigate the role of the Inositol-Requiring Enzyme 1α (Ire1α) in the development of the neocortex, particularly in the context of neuronal fate acquisition and axon-dendrite polarity establishment. The neocortex, responsible for higher cognitive functions, requires a well-regulated generation of distinct neuron subtypes within specific cortical layers, including upper and deeper layers. The role of stress regulators, like UPR-executor Ire1α, as well as canonical pathways regulating protein synthesis rates, in the context of cortical neurogenesis and acquisition of polarity have not been fully understood. Dysfunctions in these processes can lead to neurodevelopmental disorders such as autism spectrum disorders. The project had four primary goals: 1. Mechanism of Ire1α in Neuronal Fate Establishment: Investigate how Ire1α regulates the differentiation of neurons into specific cortical layers, particularly focusing on its role in determining neuronal fate, i.e. if neurons become upper or deeper layer types. 2. Ire1α in Axon-Dendrite Polarity and Neuronal Morphology: Explore the involvement of Ire1α in shaping neuronal morphology by regulating axon and dendrite formation, particularly in upper layer neurons. 3. Ire1α Interaction Partners and Translation Regulation: Identify the molecular partners of Ire1α and study its role in regulating translation processes critical for neuronal development. The aim is to understand how restoring specific signaling pathways in Ire1α knockout neurons could rescue defects in neuronal fate and polarity. 4. Translation Rates and Neuronal Development: Investigate whether global translation rates are linked to neuronal fate determination and polarity establishment in the developing neocortex. This goal seeked to uncover how Ire1α regulates protein synthesis and its impact on early and late apical progenitors. Overall, the project seeked to uncover previously unknown molecular pathways involving Ire1α that control key aspects of neurogenesis and cortical development.
Publications
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A critical period of translational control during brain development at codon resolution. Nature Structural & Molecular Biology, 29(12), 1277-1290.
Harnett, Dermot; Ambrozkiewicz, Mateusz C.; Zinnall, Ulrike; Rusanova, Alexandra; Borisova, Ekaterina; Drescher, Amelie N.; Couce-Iglesias, Marta; Villamil, Gabriel; Dannenberg, Rike; Imami, Koshi; Münster-Wandowski, Agnieszka; Fauler, Beatrix; Mielke, Thorsten; Selbach, Matthias; Landthaler, Markus; Spahn, Christian M. T.; Tarabykin, Victor; Ohler, Uwe & Kraushar, Matthew L.
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Protein translation rate determines neocortical neuron fate. Nature Communications, 15(1).
Borisova, Ekaterina; Newman, Andrew G.; Couce Iglesias, Marta; Dannenberg, Rike; Schaub, Theres; Qin, Bo; Rusanova, Alexandra; Brockmann, Marisa; Koch, Janina; Daniels, Marieatou; Turko, Paul; Jahn, Olaf; Kaplan, David R.; Rosário, Marta; Iwawaki, Takao; Spahn, Christian M. T.; Rosenmund, Christian; Meierhofer, David; Kraushar, Matthew L. ... & Ambrozkiewicz, Mateusz C.
