AI Article Synopsis
- TGFβ plays a crucial role in promoting neuronal differentiation during embryonic central nervous system development by activating specific signaling pathways that increase the expression of the cyclin-dependent kinase inhibitor Cdkn1a.* -
- In early CNS development, the transcription factor FOXG1 inhibits TGFβ-mediated effects by preventing the activation of Cdkn1a, thereby allowing cells to continue proliferating instead of differentiating.* -
- The study identifies new target genes influenced by FOXG1 and highlights the interplay between TGFβ, IGF1 signaling, and the FOXO transcription factors, suggesting that while FOXG1 is important, TGFβ signaling is likely essential for proper neuronal differentiation.*
Article Abstract
Transforming growth factor β (TGFβ)-mediated anti-proliferative and differentiating effects promote neuronal differentiation during embryonic central nervous system development. TGFβ downstream signals, composed of activated SMAD2/3, SMAD4 and a FOXO family member, promote the expression of cyclin-dependent kinase inhibitor Cdkn1a. In early CNS development, IGF1/PI3K signaling and the transcription factor FOXG1 inhibit FOXO- and TGFβ-mediated Cdkn1a transcription. FOXG1 prevents cell cycle exit by binding to the SMAD/FOXO-protein complex. In this study we provide further details on the FOXG1/FOXO/SMAD transcription factor network. We identified ligands of the TGFβ- and IGF-family, Foxo1, Foxo3 and Kcnh3 as novel FOXG1-target genes during telencephalic development and showed that FOXG1 interferes with Foxo1 and Tgfβ transcription. Our data specify that FOXO1 activates Cdkn1a transcription. This process is under control of the IGF1-pathway, as Cdkn1a transcription increases when IGF1-signaling is pharmacologically inhibited. However, overexpression of CDKN1A and knockdown of Foxo1 and Foxo3 is not sufficient for neuronal differentiation, which is probably instructed by TGFβ-signaling. In mature neurons, FOXG1 activates transcription of the seizure-related Kcnh3, which might be a FOXG1-target gene involved in the FOXG1 syndrome pathology.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122323 | PMC |
| http://dx.doi.org/10.18632/oncotarget.9545 | DOI Listing |
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