| First Author | Bugacov H | Year | 2024 |
| Journal | Development | Volume | 151 |
| Issue | 18 | PubMed ID | 39250420 |
| Mgi Jnum | J:355647 | Mgi Id | MGI:7738675 |
| Doi | 10.1242/dev.202279 | Citation | Bugacov H, et al. (2024) Dose-dependent responses to canonical Wnt transcriptional complexes in the regulation of mammalian nephron progenitors. Development 151(18) |
| abstractText | 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 beta-catenin, a transcriptional co-activator when complexed with Lef/Tcf DNA-binding partners. Using the GSK3beta inhibitor CHIR99021 (CHIR) to block GSK3beta-dependent destruction of beta-catenin, we examined dose-dependent responses to beta-catenin in mouse NPCs, using mRNA transduction to modify gene expression. Low CHIR-dependent proliferation of NPCs was blocked on beta-catenin removal, with evidence of NPCs arresting at the G2-M transition. While NPC identity was maintained following beta-catenin removal, mRNA-seq identified low CHIR and beta-catenin dependent genes. High CHIR activated nephrogenesis. Nephrogenic programming was dependent on Lef/Tcf factors and beta-catenin transcriptional activity. Molecular and cellular features of early nephrogenesis were driven in the absence of CHIR by a mutated stabilized form of beta-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. |
