Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance

Neha Zutshi, Bhopal C. Mohapatra, Pinaki Mondal, Wei An, Benjamin T. Goetz, Shuo Wang, Sicong Li, Matthew D. Storck, David F. Mercer, Adrian R. Black, Sarah P. Thayer, Jennifer D. Black, Chi Lin, Vimla Band, Hamid Band

Research output: Contribution to journalArticlepeer-review

Abstract

Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5Hi ISCs with transient expansion of the Lgr5Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.

Original languageEnglish (US)
Article number109912
JournaliScience
Volume27
Issue number6
DOIs
StatePublished - Jun 21 2024

Keywords

  • Biochemistry
  • Biological sciences
  • Cell biology
  • Molecular biology
  • Natural sciences
  • Stem cells research

ASJC Scopus subject areas

  • General

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