Alveolar progenitor differentiation and lactation depends on paracrine inhibition of notch via ROBO1/CTNNB1/JAG1

ABSTRACT In the mammary gland, how alveolar progenitor cells are recruited to fuel tissue growth with each estrus cycle and pregnancy remains poorly understood. Here, we identify a regulatory pathway that controls alveolar progenitor differentiation and lactation by governing Notch activation in mouse. Loss of Robo1 in the mammary gland epithelium activates Notch signaling, which expands the alveolar progenitor cell population at the expense of alveolar differentiation, resulting in compromised lactation. ROBO1 is expressed in both luminal and basal cells, but loss of Robo1 in basal cells results in the luminal differentiation defect. In the basal compartment, ROBO1 inhibits the expression of Notch ligand Jag1 by regulating β-catenin (CTNNB1), which binds the Jag1 promoter. Together, our studies reveal how ROBO1/CTTNB1/JAG1 signaling in the basal compartment exerts paracrine control of Notch signaling in the luminal compartment to regulate alveolar differentiation during pregnancy.

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Role of Jagged1-mediated Notch Signaling Activation in the Differentiation and Stratification of the Human Limbal Epithelium

Cells ◽

10.3390/cells9091945 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1945

Author(s):

Sheyla González ◽

Maximilian Halabi ◽

David Ju ◽

Matthew Tsai ◽

Sophie X. Deng

Keyword(s):

Notch Signaling ◽

Progenitor Cell ◽

Basal Layer ◽

Notch Signaling Pathway ◽

Basal Cells ◽

Proliferation Markers ◽

Limbal Epithelium ◽

Asymmetric Divisions ◽

Signaling Activation

The Notch signaling pathway plays a key role in proliferation and differentiation. We investigated the effect of Jagged 1 (Jag1)-mediated Notch signaling activation in the human limbal stem/progenitor cell (LSC) population and the stratification of the limbal epithelium in vitro. After Notch signaling activation, there was a reduction in the amount of the stem/progenitor cell population, epithelial stratification, and expression of proliferation markers. There was also an increase of the corneal epithelial differentiation. In the presence of Jag1, asymmetric divisions were decreased, and the expression pattern of the polarity protein Par3, normally present at the apical-lateral membrane of basal cells, was dispersed in the cells. We propose a mechanism in which Notch activation by Jag1 decreases p63 expression at the basal layer, which in turn reduces stratification by decreasing the number of asymmetric divisions and increases differentiation.

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Age-Dependent Activation and Neuronal Differentiation of Lgr5+ Basal Cells in Injured Olfactory Epithelium via Notch Signaling Pathway

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.602688 ◽

2020 ◽

Vol 12 ◽

Author(s):

Xuewen Li ◽

Meimei Tong ◽

Li Wang ◽

Yumei Qin ◽

Hongmeng Yu ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Sensory Neurons ◽

Olfactory Epithelium ◽

Three Dimensional ◽

Notch Signaling Pathway ◽

Basal Cells ◽

Aged Mice ◽

Age Dependent ◽

Notch Activation

Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.

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Elf5 Regulates Mammary Gland Stem/Progenitor Cell Fate by Influencing Notch Signaling

Stem Cells ◽

10.1002/stem.1112 ◽

2012 ◽

Vol 30 (7) ◽

pp. 1496-1508 ◽

Cited By ~ 77

Author(s):

Rumela Chakrabarti ◽

Yong Wei ◽

Rose-Anne Romano ◽

Christina DeCoste ◽

Yibin Kang ◽

...

Keyword(s):

Mammary Gland ◽

Notch Signaling ◽

Cell Fate ◽

Progenitor Cell

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Sca-1pos Cells in the Mouse Mammary Gland Represent an Enriched Progenitor Cell Population

Developmental Biology ◽

10.1006/dbio.2002.0625 ◽

2002 ◽

Vol 245 (1) ◽

pp. 42-56 ◽

Cited By ~ 358

Author(s):

Bryan E. Welm ◽

Stacey B. Tepera ◽

Teresa Venezia ◽

Timothy A. Graubert ◽

Jeffrey M. Rosen ◽

...

Keyword(s):

Mammary Gland ◽

Cell Population ◽

Progenitor Cell ◽

Mouse Mammary Gland ◽

Progenitor Cell Population

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Faculty Opinions recommendation of IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2428956.2895065 ◽

2010 ◽

Author(s):

Jay Kolls

Keyword(s):

Cell Population ◽

Progenitor Cell ◽

Cytokine Responses ◽

Progenitor Cell Population

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Faculty Opinions recommendation of Fgf10-positive cells represent a progenitor cell population during lung development and postnatally.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718213393.793490889 ◽

2014 ◽

Author(s):

Christian Mühlfeld

Keyword(s):

Cell Population ◽

Lung Development ◽

Progenitor Cell ◽

Progenitor Cell Population

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Current Views on the Roles of O-Glycosylation in Controlling Notch-Ligand Interactions

Biomolecules ◽

10.3390/biom11020309 ◽

2021 ◽

Vol 11 (2) ◽

pp. 309

Author(s):

Wataru Saiki ◽

Chenyu Ma ◽

Tetsuya Okajima ◽

Hideyuki Takeuchi

Keyword(s):

Notch Signaling ◽

100Th Anniversary ◽

Notch Receptor ◽

Notch Receptors ◽

Evolutionarily Conserved ◽

Future Challenges ◽

Ligand Interactions ◽

Epidermal Growth ◽

Notch Activation ◽

Human Specific

The 100th anniversary of Notch discovery in Drosophila has recently passed. The Notch is evolutionarily conserved from Drosophila to humans. The discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future. Notch receptors are responsible for cell-to-cell signaling. They are activated by cell-surface ligands located on adjacent cells. Notch activation plays an important role in determining the fate of cells, and dysregulation of Notch signaling results in numerous human diseases. Notch receptors are primarily activated by ligand binding. Many studies in various fields including genetics, developmental biology, biochemistry, and structural biology conducted over the past two decades have revealed that the activation of the Notch receptor is regulated by unique glycan modifications. Such modifications include O-fucose, O-glucose, and O-N-acetylglucosamine (GlcNAc) on epidermal growth factor-like (EGF) repeats located consecutively in the extracellular domain of Notch receptors. Being fine-tuned by glycans is an important property of Notch receptors. In this review article, we summarize the latest findings on the regulation of Notch activation by glycosylation and discuss future challenges.

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TAMI-36. TAMEP ARE BRAIN TUMOR PARENCHYMAL CELLS CONTROLLING NEOPLASTIC ANGIOGENESIS AND PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noab196.820 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi205-vi206

Author(s):

Roland Kälin ◽

Linzhi Cai ◽

Yuping Li ◽

Ines Hellmann ◽

Rainer Glass

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Single Cell ◽

Disease Progression ◽

Progenitor Cell ◽

Local Environment ◽

Lineage Tracing ◽

Immunofluorescence Analysis ◽

Progenitor Cell Population ◽

Parenchymal Cells

Abstract Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor-parenchymal cells may promote specific phases of disease-progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Strikingly, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell-population, by conditional Sox2-knockout, drastically reduced glioblastoma-vascularization and -size. TAMEP manipulation profoundly altered vessel function and strongly attenuated the blood-tumor barrier. Hence, our data indicate TAMEP and their progenitors as new targets for glioblastoma therapy.

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