title: Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis.
abstract: Mammary epithelium is comprised of an inner layer of luminal epithelial cells and an outer layer of contractile myoepithelial cells with mesenchymal properties. These two compartments interact throughout mammary morphogenesis to form branching ducts during puberty and terminate in secretory alveoli during lactation. It is not known how the myoepithelial cell lineage is specified, nor how signals in myoepithelial cells contribute to lactogenesis. Here, we show that Numb and Numbl are enriched in mammary myoepithelial cells, with their expression peaking during pregnancy. We use conditional Numb- and Numbl-knockout mouse models to demonstrate that loss of Numb/Numbl compromised the myoepithelial layer and expanded the luminal layer, led epithelial cells to undergo epithelial-to-mesenchymal transition, and resulted in lactation failure as a result of abnormal alveolar formation during pregnancy. Numb and Numbl function via repression of the Notch signaling pathway and of the p53-p21 axis during mammary gland development. These findings highlight the importance of Numb and Numbl in the control of myoepithelial cell fate determination, epithelial identity, and lactogenesis.-Zhang Y., Li, F., Song, Y., Sheng, X., Ren, F., Xiong, K., Chen, L., Zhang, H., Liu, D., Lengner, C. J., Xue, L., Yu, Z. Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis.
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Fengyin
authors.initials: F
authors.lastname: Li
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Song
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Xiaole
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health and.
authors.forename: Fazheng
authors.initials: F
authors.lastname: Ren
authors.affiliation: Department of Radiation Oncology, Peking University Third Hospital-Medical Research Center, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xiong
authors.affiliation: Department of Animal Science, Southwest University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Cell Biology and Tumor Biology and Department of Anatomy, Histology, and Embryology, Peking University Health Science Center, Beijing, China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Breast Surgery, The Third Affiliated Hospital, Kunming Medical University, Yunnan, China; and.
authors.forename: Dequan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biomedical Sciences, Department of Cell and Developmental Biology, and Institute for Regenerative Medicine, University of Pennsylvania Medical Research Center, Philadelphia, Pennsylvania, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.affiliation: Department of Radiation Oncology, Peking University Third Hospital-Medical Research Center, Beijing, China; lixiangxue@bjmu.eu.cn.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.affiliation: Beijing Advanced Innovation Center for Food Nutrition and Human Health and State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China; zyu@cau.edu.cn.
authors.forename: Zhengquan
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000166:cytology; D009130:Muscle, Smooth / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C530266:NUMBL protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C106293:Numb protein, mouse; C106292:Numbl protein, mouse
keywords: EMT; Notch signaling pathway; mammary gland development; p53