The canonical Notch/RBP-J signaling pathway controls the balance of cell lineages in mammary epithelium during pregnancy

Mammary alveoli are composed of luminal (secretory) and basal (myoepithelial) cells, which are descendants of a common stem cell. This study addressed the role of RBP-J-dependent Notch signaling in the formation, maintenance and cellular composition of alveoli during pregnancy. For this purpose, the...

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Bibliographic Details
Published in:Developmental biology 2006-05, Vol.293 (2), p.565-580
Main Authors: Buono, Krista D., Robinson, Gertraud W., Martin, Cyril, Shi, Shaolin, Stanley, Pamela, Tanigaki, Kenji, Honjo, Tasuku, Hennighausen, Lothar
Format: Article
Language:English
Subjects:
Animals
Basal cells
Base Sequence
Cell Proliferation
Cytokeratins
DNA - genetics
Epithelial Cells - cytology
Epithelial Cells - metabolism
Estrogen Receptor alpha - metabolism
Female
Immunoglobulin J Recombination Signal Sequence-Binding Protein - deficiency
Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism
Keratins - metabolism
Mammary epithelium
Mammary Glands, Animal - cytology
Mammary Glands, Animal - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Mice, Transgenic
Models, Biological
Myoepithelium
Notch
Phosphoproteins - metabolism
Pofut1
Pregnancy
RBP-J
Receptors, Notch - metabolism
Signal Transduction
Stem Cells - cytology
Stem Cells - metabolism
Trans-Activators - metabolism
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Summary:Mammary alveoli are composed of luminal (secretory) and basal (myoepithelial) cells, which are descendants of a common stem cell. This study addressed the role of RBP-J-dependent Notch signaling in the formation, maintenance and cellular composition of alveoli during pregnancy. For this purpose, the genes encoding RBP-J, the shared transcriptional mediator of Notch receptors, and Pofut1, a fucosyltransferase required for the activity of Notch receptors, were deleted in mammary progenitor cells in the mouse using Cre-mediated recombination. Loss of RBP-J and Pofut1 led to an accumulation of basal cell clusters characterized by the presence of cytokeratins (K5) and K14 and smooth muscle actin (SMA) during pregnancy. Hormonal stimulation of mutant tissue induced the expression of the basal cell transcription factor p63 in luminal cells and excessive proliferation of basal cells. A transient enrichment of K6-positive luminal cells was observed upon hormonal treatment suggesting a temporary arrest at an immature stage prior to transdifferentiation and expansion as basal cells. Despite the extensive proliferation of RBP-J-null basal cells during pregnancy, hormonal withdrawal during involution resulted in complete remodeling and the restoration of normal tissue architecture. We propose that the Notch-RBP-J pathway regulates alveolar development during pregnancy by maintaining luminal cell fate and preventing uncontrolled basal cell proliferation.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2006.02.043