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Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages

Nature Cell Biology volume 15, pages 451–460 (2013)Cite this article

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Abstract

Notch signalling is implicated in stem and progenitor cell fate control in numerous organs. Using conditional in vivo genetic labelling we traced the fate of cells expressing the Notch2 receptor paralogue and uncovered the existence of two previously unrecognized mammary epithelial cell lineages that we term S (Small) and L (Large). S cells appear in a bead-on-a-string formation and are embedded between the luminal and basal/myoepithelial layers in a unique reiterative pattern, whereas single or paired L cells appear among ductal and alveolar cells. Long-term lineage tracing and functional studies indicate that S and L cells regulate ipsi- and contralateral spatial placement of tertiary branches and formation of alveolar clusters. Our findings revise present models of mammary epithelial cell hierarchy, reveal a hitherto undescribed mechanism regulating branching morphogenesis and may have important implications for identification of the cell-of-origin of distinct breast cancer subtypes.

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Figure 1: Notch2+ lineages define distinct subsets of MECs.
Figure 2: Expression of lineage-specific markers in L and S cells.
Figure 3: The fate of pubertal Notch2+ lineages in pregnancy.
Figure 4: The fate of pubertal Notch2+ lineages during lactation and involution.
Figure 5: Ablation of pubertal Notch2+ lineages impairs formation of tertiary branches and alveolar clusters.
Figure 6: Proposed revised model of the MEC lineages and differentiation hierarchy.

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Acknowledgements

The authors would like to thank J. S. Brugge for her long-standing and very generous technical and theoretical advice throughout this project as well as for critical reading of the manuscript. We thank A. Shiang-Ru Kaanta for technical advice and critical reading of the manuscript and also A. Louvi for critical reading of the manuscript. In addition, we would also like to thank the Nikon Imaging Center at Harvard Medical School for help with light microscopy and the Animal Facility at Harvard Center for Comparative Medicine for helping in the maintenance and care of the transgenic animals. This work was supported by grants from the NIH to S.A-T.

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    Sanja Šale & Spyros Artavanis-Tsakonas

  2. Department of Genetics and Developmental Biology, Institute Curie, Paris VI, France

    Daniel Lafkas

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  1. Sanja Šale
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Contributions

S.S. conceptualized, designed and performed all experiments and data analysis; D.L. contributed to transplantation experiments; S.A-T. conceived the study. S.S. and S.A-T. wrote the paper.

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Correspondence to Spyros Artavanis-Tsakonas.

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The authors declare no competing financial interests.

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Šale, S., Lafkas, D. & Artavanis-Tsakonas, S. Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15, 451–460 (2013). https://doi.org/10.1038/ncb2725

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