| First Author | Fischer JM | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 43 | Pages | 12192-12197 |
| PubMed ID | 27791005 | Mgi Jnum | J:238805 |
| Mgi Id | MGI:5824179 | Doi | 10.1073/pnas.1611980113 |
| Citation | Fischer JM, et al. (2016) Single cell lineage tracing reveals a role for TgfbetaR2 in intestinal stem cell dynamics and differentiation. Proc Natl Acad Sci U S A 113(43):12192-12197 |
| abstractText | Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor beta receptor 2 (TgfbetaR2) mutation to show cell autonomous effects of TgfbetaR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfbetaR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfbeta signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfbetaR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfbeta signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfbeta signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfbeta signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation. |
