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  4. Pum2 and TDP-43 refine area-specific cytoarchitecture post-mitotically and modulate translation of Sox5, Bcl11b, and Rorb mRNAs in developing mouse neocortex
 
research article

Pum2 and TDP-43 refine area-specific cytoarchitecture post-mitotically and modulate translation of Sox5, Bcl11b, and Rorb mRNAs in developing mouse neocortex

Harb, Kawssar
•
Richter, Melanie
•
Neelagandan, Nagammal  
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March 9, 2022
Elife

In 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.

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Type
research article
DOI
10.7554/eLife.55199
10.7554/eLife.55199.sa0
10.7554/eLife.55199.sa1
10.7554/eLife.55199.sa2
Web of Science ID

WOS:000768256200001

Author(s)
Harb, Kawssar
Richter, Melanie
Neelagandan, Nagammal  
Magrinelli, Elia
Harfoush, Hend
Kuechler, Katrin
Henis, Melad
Hermanns-Borgmeyer, Irm
de Anda, Froylan Calderon
Duncan, Kent
Date Issued

2022-03-09

Publisher

eLIFE SCIENCES PUBL LTD

Published in
Elife
Volume

11

Article Number

e55199

Subjects

Biology

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Life Sciences & Biomedicine - Other Topics

•

rna binding proteins

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arealization

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cell type specification

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translation

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mouse neocortex

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molecular determinants

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mouse

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subcortical projection neurons

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posttranscriptional regulation

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binding protein

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mice show

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pumilio

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expression

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genes

•

identification

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complex

•

target

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPNAE  
Available on Infoscience
March 28, 2022
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/186735
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