The role of cellular stress-associated protein Ire1α in the development of the cerebral cortex.

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Formation of cortical architecture during development is fundamental for mature brain connectivity. Neurons of upper layers preferentially establish intracortical connections, whereas the axons of deeper layer neurons form subcerebral connections. Besides formation of axonal tracts enabling communication between different brain regions, the executive role of the cerebral cortex requires a unidirectional flow of action potentials on highly polarized neurons. Acquisition of neuronal cell fate and axon-dendrite polarity during development is therefore crucial for uninterrupted cortical functions. We have recently discovered that Inositol-Requiring Enzyme 1, Ire1α, is necessary for acquisition of upper layer neuronal fate and establishment of polarized neuronal morphology. Moreover, we have preliminary data that Ire1α acts as a canonical regulator of protein translation in developing neurons. We propose an experimental plan to reveal the molecular mechanisms of Ire1α-mediated neuronal fate and polarity establishment. It includes the analysis of the cytoskeleton stability, thorough investigation of neurogenesis in dorsal forebrain-specific Ire1α KO mice, mass-spectrometry and deep RNA-sequencing approaches to delineate Ire1α-dependent cellular signaling during corticogenesis. We also propose to investigate the end-point consequences of Ire1α loss for cortical connectivity using a cutting-edge whole brain imaging technique. Further, we plan to investigate the global mechanisms of translational rate regulation and its involvement in establishment of neuronal cell fate and polarization of neurons. Our research will significantly contribute to the understanding of signaling cascades at play during brain development, but also to broadening the scope of Ire1α involvement in biological processes, previously majorly linked to cellular stress and pathologies, among others neurodegeneration.