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Publication : Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland.

First Author  Wang Z Year  2023
Journal  Cell Death Dis Volume  14
Issue  10 Pages  675
PubMed ID  37833248 Mgi Jnum  J:344095
Mgi Id  MGI:7541788 Doi  10.1038/s41419-023-06184-2
Citation  Wang Z, et al. (2023) Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland. Cell Death Dis 14(10):675
abstractText  Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2-Stat3-Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.
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