Harb, KawssarRichter, MelanieNeelagandan, NagammalMagrinelli, EliaHarfoush, HendKuechler, KatrinHenis, MeladHermanns-Borgmeyer, Irmde Anda, Froylan CalderonDuncan, Kent2022-03-282022-03-282022-03-282022-03-0910.7554/eLife.5519910.7554/eLife.55199.sa010.7554/eLife.55199.sa110.7554/eLife.55199.sa2https://infoscience.epfl.ch/handle/20.500.14299/186735WOS:000768256200001In the neocortex, functionally distinct areas process specific types of information. Area identity is established by morphogens and transcriptional master regulators, but downstream mechanisms driving area-specific neuronal specification remain unclear. Here, we reveal a role for RNA-binding proteins in defining area-specific cytoarchitecture. Mice lacking Pum2 or overexpressing human TDP-43 show apparent 'motorization' of layers IV and V of primary somatosensory cortex (S1), characterized by dramatic expansion of cells co-expressing Sox5 and Bcl11b/Ctip2, a hallmark of subcerebral projection neurons, at the expense of cells expressing the layer IV neuronal marker Ror beta. Moreover, retrograde labeling experiments with cholera toxin B in Pum2; Emx1-Cre and TDP43(A315T) mice revealed a corresponding increase in subcerebral connectivity of these neurons in S1. Intriguingly, other key features of somatosensory area identity are largely preserved, suggesting that Pum2 and TDP-43 may function in a downstream program, rather than controlling area identity per se. Transfection of primary neurons and in utero electroporation (IUE) suggest cell-autonomous and post-mitotic modulation of Sox5, Bcl11b/Ctip2, and Ror beta levels. Mechanistically, we find that Pum2 and TDP-43 directly interact with and affect the translation of mRNAs encoding Sox5, Bcl11b/Ctip2, and Ror beta. In contrast, effects on the levels of these mRNAs were not detectable in qRT-PCR or single-molecule fluorescent in situ hybridization assays, and we also did not detect effects on their splicing or polyadenylation patterns. Our results support the notion that post-transcriptional regulatory programs involving translational regulation and mediated by Pum2 and TDP-43 contribute to elaboration of area-specific neuronal identity and connectivity in the neocortex.BiologyLife Sciences & Biomedicine - Other Topicsrna binding proteinsarealizationcell type specificationtranslationmouse neocortexmolecular determinantsmousesubcortical projection neuronsposttranscriptional regulationbinding proteinmice showpumilioexpressiongenesidentificationcomplextargettext::journal::journal article::research article