Prohaptoglobin inhibits the transforming growth factor-β-induced epithelial-to-mesenchymal transition in vitro by increasing Smad1/5 activation and suppressing the Smad2/3 signaling pathway in SK-Hep1 liver cancer cells

Oh, Mi-Kyung; Joo, Hansol; Kim, In-Sook

doi:10.1371/journal.pone.0266409

Cited by 2 publications

(2 citation statements)

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“…4B). Indeed, phosphorylation of SMAD1/5 and SMAD2/3 is mutually inhibited and SMAD2/3 double knockout caused high levels of pSMAD1/5 and ID1 expression, leading to defect of neuroectodermal patterning 52–54 . Thus, these results demonstrate that complete loss of MeCP2 function causes excessive activation of the BMP signaling pathway during neuroectodermal differentiation of brain organoids.…”

Section: Resultsmentioning

confidence: 73%

“…Inhibition of BMP pathway is critical for the fate conversion of stem cells into neuroectoderm lineage by triggering expression of key transcription factors such as PAX6. 50,51,55,56,92,93 PAX6 further reinforces BMP inhibition through miR135b-dependent translational regulation, which accelerates neural induction and niche formation for NPCs 53 . Intriguingly, a recent report suggested the negative correlation between MeCP2 and miR135b expression.…”

Section: Discussionmentioning

confidence: 88%

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MeCP2 dysfunction prevents proper BMP signaling and neural progenitor expansion in brain organoid

Hong

Yoon

Park

et al. 2023

Ann Clin Transl Neurol

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Objectives Sporadic mutations in MeCP2 are a hallmark of Rett syndrome (RTT). Many RTT brain organoid models have exhibited pathogenic phenotypes such as decreased spine density and small size of soma with altered electrophysiological signals. However, previous models are mainly focused on the phenotypes observed in the late phase and rarely provide clues for the defect of neural progenitors which generate different types of neurons and glial cells. Methods We newly established the RTT brain organoid model derived from MeCP2‐truncated iPS cells which were genetically engineered by CRISPR/Cas9 technology. By immunofluorescence imaging, we studied the development of NPC pool and its fate specification into glutamatergic neurons or astrocytes in RTT organoids. By total RNA sequencing, we investigated which signaling pathways were altered during the early brain development in RTT organoids. Results Dysfunction of MeCP2 caused the defect of neural rosette formation in the early phase of cortical development. In total transcriptome analysis, BMP pathway‐related genes are highly associated with MeCP2 depletion. Moreover, levels of pSMAD1/5 and BMP target genes are excessively increased, and treatment of BMP inhibitors partially rescues the cell cycle progression of neural progenitors. Subsequently, MeCP2 dysfunction reduced the glutamatergic neurogenesis and induced overproduction of astrocytes. Nevertheless, early inhibition of BMP pathway rescued VGLUT1 expression and suppressed astrocyte maturation. Interpretation Our results demonstrate that MeCP2 is required for the expansion of neural progenitor cells by modulating BMP pathway at early stages of development, and this influence persists during neurogenesis and gliogenesis at later stages of brain organoid development.

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Section: Resultsmentioning

confidence: 73%