Pum2 and TDP-43 refine area-specific cytoarchitecture post-mitotically and modulate translation of Sox5, Bcl11b , and Rorb mRNAs in developing mouse neocortex.
Kawssar HarbMelanie RichterNagammal NeelagandanElia MagrinelliHend HarfoushKatrin KuechlerMelad HenisIrm Hermanns-BorgmeyerFroylan Calderon de AndaKent DuncanPublished in: eLife (2022)
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 Rorβ. 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 Rorβ levels. Mechanistically, we find that Pum2 and TDP-43 directly interact with and affect the translation of mRNAs encoding Sox5, Bcl11b/Ctip2, and Rorβ. 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.
Keyphrases
- transcription factor
- amyotrophic lateral sclerosis
- single molecule
- stem cells
- induced apoptosis
- spinal cord
- gene expression
- single cell
- cell cycle arrest
- healthcare
- magnetic resonance
- escherichia coli
- functional connectivity
- bone marrow
- living cells
- cell proliferation
- public health
- resting state
- cerebral ischemia
- magnetic resonance imaging
- quality improvement
- white matter
- signaling pathway
- spinal cord injury
- metabolic syndrome
- social media
- endoplasmic reticulum stress
- subarachnoid hemorrhage
- insulin resistance
- cell death
- quantum dots
- working memory
- heat shock protein
- diffusion weighted imaging
- image quality
- contrast enhanced