Ire1α-Regulated Rate of mRNA Translation is Required for Acquisition of Identity and Polarity in Upper Layer Cortical Neurons

Establishment of cortical layers and axon-dendrite polarity in neurons is fundamental for brain connectivity. Here, we present that timed mRNA translation control by Inositol-Requiring Enzyme 1α, Ire1α, is necessary for acquisition of upper layer neuronal identity and a single axon. We demonstrate that Ire1α acts as a canonical regulator of global protein synthesis in developing cortical neurons, controlling the level of actively translating ribosomes, expression of translation factors, and ribosomal proteins. Translation rates distinguish early and late neuronal progenitors and early- and late-born postmitotic neurons, indicative of developmental stage- and differentiation-specific requirements for protein synthesis rates in the formation of upper and deeper cortical layers. We demonstrate that specification and polarization of upper layer neurons is uniquely sensitive to translation rate, in contrast to deep layer neurons. Our data shed light onto the post-transcriptional source of cellular diversity in the developing cortex and unveils stress-independent homeostatic functions of Ire1α.