Dose-dependent responses to canonical Wnt transcriptional complexes in the regulation of mammalian nephron progenitors.
Development
; 2024 Sep 09.
Article
em En
| MEDLINE
| ID: mdl-39250420
ABSTRACT
In vivo and in vitro studies argue that concentration dependent Wnt signaling regulates mammalian nephron progenitor cell (NPC) programs. Canonical Wnt signaling is regulated through the stabilization of ß-catenin, a transcriptional co-activator when complexed with Lef/Tcf DNA binding partners. Utilizing the GSK3ß inhibitor CHIR99021 (CHIR), to block GSK3ß-dependent destruction of ß-catenin, we examined dose-dependent responses to ß-catenin in NPCs, using mRNA transduction to modify gene expression. Low CHIR-dependent proliferation of NPCs was blocked on ß-catenin removal with evidence of NPCs arresting at the G2-M transition. While NPC identity was maintained following ß-catenin removal, mRNA-seq identified low CHIR and ß-catenin dependent genes. High CHIR activated nephrogenesis. Nephrogenic programming was dependent on Lef/Tcf factors and ß-catenin transcriptional activity. Molecular and cellular features of early nephrogenesis were driven in the absence of CHIR by a mutated, stabilized form of ß-catenin. Chromatin association studies indicate low and high CHIR response genes are likely direct targets of canonical Wnt transcriptional complexes. Together these studies provide evidence for concentration dependent Wnt-signaling in the regulation of NPCs and provide new insight into Wnt targets initiating mammalian nephrogenesis.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article