Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland

A. Lilja, V. Rodilla, M. Huyghe, E.B. Hannezo, C. Landragin, O. Renaud, O. Leroy, S. Rulands, B. Simons, S. Fré, Nature Cell Biology 20 (2018) 677–687.

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Abstract
Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.
Publishing Year
Date Published
2018-05-21
Journal Title
Nature Cell Biology
Acknowledgement
This work was supported by Paris Sciences et Lettres (PSL* Research University), the French National Research Agency (ANR) grant no.s ANR-15-CE13-0013-01, the Canceropole Ile-de-France (grant no. 2015-2-APD-01-ICR-1) and by Labex DEEP ANR-Number 11-LBX-0044 (to S.F.), the Wellcome Trust (grant no. 098357/Z/12/Z to B.D.S. and 110326/Z/15/Z to E.H.). A.M.L. was funded by a post-doctoral fellowship from the Fondation de France. E.H. was funded by a Junior Research Fellowship from Trinity College (Cambridge University), a Sir Henry Wellcome Fellowship from the Wellcome Trust, and acknowledges the Bettencourt-Schueller Young Researcher Prize for support. The PICT-IBiSA imaging platform was funded by ANR-10-INBS-04 (France-BioImaging), ANR-11 BSV2 012 01, ERC ZEBRATECTUM no. 311159, ARC SFI20121205686 and the Schlumberger Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Volume
20
Issue
6
Page
677 - 687
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Lilja A, Rodilla V, Huyghe M, et al. Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland. Nature Cell Biology. 2018;20(6):677-687. doi:10.1038/s41556-018-0108-1
Lilja, A., Rodilla, V., Huyghe, M., Hannezo, E. B., Landragin, C., Renaud, O., … Fré, S. (2018). Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland. Nature Cell Biology, 20(6), 677–687. https://doi.org/10.1038/s41556-018-0108-1
Lilja, Anna, Veronica Rodilla, Mathilde Huyghe, Edouard B Hannezo, Camille Landragin, Olivier Renaud, Olivier Leroy, Steffen Rulands, Benjamin Simons, and Silvia Fré. “Clonal Analysis of Notch1-Expressing Cells Reveals the Existence of Unipotent Stem Cells That Retain Long-Term Plasticity in the Embryonic Mammary Gland.” Nature Cell Biology 20, no. 6 (2018): 677–87. https://doi.org/10.1038/s41556-018-0108-1.
A. Lilja et al., “Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland,” Nature Cell Biology, vol. 20, no. 6, pp. 677–687, 2018.
Lilja A, Rodilla V, Huyghe M, Hannezo EB, Landragin C, Renaud O, Leroy O, Rulands S, Simons B, Fré S. 2018. Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland. Nature Cell Biology. 20(6), 677–687.
Lilja, Anna, et al. “Clonal Analysis of Notch1-Expressing Cells Reveals the Existence of Unipotent Stem Cells That Retain Long-Term Plasticity in the Embryonic Mammary Gland.” Nature Cell Biology, vol. 20, no. 6, Nature Publishing Group, 2018, pp. 677–87, doi:10.1038/s41556-018-0108-1.

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