Dose-dependent responses to canonical Wnt transcriptional complexes in the regulation of mammalian nephron progenitors.

Autor:	Bugacov H; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.; Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Der B; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.; Department of Urology, Faculty of Medicine, Semmelweis University, Budapest 1082, Hungary.; Institute of Translational Medicine, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary., Briantseva BM; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA., Guo Q; Discovery Biomarkers, Amgen Research, 1 Amgen Center Drive, Thousand Oaks, CA 91320, USA., Kim S; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA., Lindström NO; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA., McMahon AP; Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2024 Sep 15; Vol. 151 (18). Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1242/dev.202279
Abstrakt:	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 β-catenin, a transcriptional co-activator when complexed with Lef/Tcf DNA-binding partners. Using the GSK3β inhibitor CHIR99021 (CHIR) to block GSK3β-dependent destruction of β-catenin, we examined dose-dependent responses to β-catenin in mouse NPCs, using mRNA transduction to modify gene expression. Low CHIR-dependent proliferation of NPCs was blocked on β-catenin removal, with evidence of NPCs arresting at the G2-M transition. While NPC identity was maintained following β-catenin removal, mRNA-seq identified low CHIR and β-catenin dependent genes. High CHIR activated nephrogenesis. Nephrogenic programming was dependent on Lef/Tcf factors and β-catenin transcriptional activity. Molecular and cellular features of early nephrogenesis were driven in the absence of CHIR by a mutated stabilized form of β-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. Competing Interests: Competing interests A.P.M. is a consultant or scientific advisor to Novartis, eGENESIS, Trestle Biotherapeutics and IVIVA Medical. (© 2024. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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