Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance
In: iScience, Jg. 27 (2024), Heft 6, S. 109912-
Online
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Zugriff:
Summary: 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.
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Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance
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Autor/in / Beteiligte Person: | Zutshi, Neha ; Mohapatra, Bhopal C. ; Mondal, Pinaki ; An, Wei ; Goetz, Benjamin T. ; Wang, Shuo ; Li, Sicong ; Storck, Matthew D. ; Mercer, David F. ; Black, Adrian R. ; Thayer, Sarah P. ; Black, Jennifer D. ; Lin, Chi ; Band, Vimla ; Band, Hamid |
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Zeitschrift: | iScience, Jg. 27 (2024), Heft 6, S. 109912- |
Veröffentlichung: | Elsevier, 2024 |
Medientyp: | academicJournal |
ISSN: | 2589-0042 (print) |
DOI: | 10.1016/j.isci.2024.109912 |
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