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Abstract: TH-PO383

β-Catenin Phosphorylation at Ser552 Impairs Expression of β-Catenin-TCF/LEF Target Genes in Mouse Collecting Duct

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Ou, Shuo-Ming, National Institutes of Health, Bethesda, Maryland, United States
  • Kikuchi, Hiroaki, National Institutes of Health, Bethesda, Maryland, United States
  • Chen, Lihe, National Institutes of Health, Bethesda, Maryland, United States
  • Chou, Chung-Lin, National Institutes of Health, Bethesda, Maryland, United States
  • Knepper, Mark A., National Institutes of Health, Bethesda, Maryland, United States
Background

Prior phospho-proteomics studies in both cultured and native collecting duct cells showed that vasopressin strongly increases phosphorylation of β-catenin at Ser552 in a protein kinase A (PKA)-dependent manner. In contrast to the N-terminal sites of β-catenin that are phosphorylated as part of canonical Wnt signaling, little is known about the role of Ser552 phosphorylation.

Methods

To address its role in the mature renal collecting duct, we have inserted an Ser552Ala mutation in mice using CRISPR-Cas9.

Results

The mutation did not affect the abundance of the vasopressin-regulated water channel aquaporin-2 (AQP2), urinary osmolality, serum chemistries, and there were no abnormalities of structure of collecting ducts or kidneys or other organs. RNA-seq in microdissected cortical collecting ducts (CDs) of unstressed mice revealed relatively few transcripts that underwent changes in abundance, and no changes in abundances of mRNAs coding for major collecting duct transport proteins, indicative of sustained collecting-duct differentiation. However, when stressed by vasopressin infusion, RNA-seq in microdissected cortical CDs revealed extensive changes in the transcriptome in response to the Ser552Ala mutation, associated with increases in transcriptional targets of the Wnt/β-catenin/TCF pathway. Enriched Gene Ontology-Biological Process terms included “cell development“, “collecting duct development“, “ureteric bud development“ and “Wnt signaling pathway“.

Conclusion

Overall, vasopressin-mediated phosphorylation of β-catenin at S552 appears to serve as an “off-switch” for the Wnt/β-catenin/TCF pathway in the collecting duct in the presence of high levels of vasopressin.

Funding

  • Other NIH Support