Ire1α-Regulated mRNA Translation Rate Controls the Identity and Polarity of Upper Layer Cortical Neurons

Evolutionary expansion of the neocortex is associated with the increase in upper layer neurons. Here, we present Inositol-Requiring Enzyme 1, Ire1, as an essential determinant of upper layer fate, neuronal polarization and cortical lamination. We demonstrate a non-canonical function of Ire1 in the regulation of global translation rates in the developing neocortex through its dynamic interaction with the ribosome and regulation of eIF4A1 and eEF-2 expression. Inactivation of Ire1 engenders lower protein synthesis rates associated with stalled ribosomes and decreased number of translation start sites. We show unique sensitivity of upper layer fate to translation rates. Whereas eEF-2 is required for cortical lamination, eIF4A1 regulates acquisition of upper layer fate downstream of Ire1 in a mechanism of translational control dependent on 5UTR-embedded structural elements in fate determinant genes. Our data unveil developmental regulation of ribosome dynamics as post-transcriptional mechanisms orchestrating neuronal diversity establishment and assembly of cortical layers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/449563v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@115a09aorg.highwire.dtl.DTLVardef@e30d2dorg.highwire.dtl.DTLVardef@763b27org.highwire.dtl.DTLVardef@2586e9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISmall molecule screening reveals Ire1 upstream of upper layer neuronal identity C_LIO_LIPolarization and proper lamination of layer II/III neurons require Ire1 C_LIO_LIDevelopment of upper layers requires high translation rates driven by eIF4A1 and eEF-2 downstream of Ire1 C_LIO_LIeIF4A1-dependent Satb2 mRNA translation initiation is a mechanism of upper layer fate acquisition C_LI