title: Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2.
abstract: The key signaling networks regulating mammary stem cells are poorly defined. The leucine-rich repeat containing G protein-coupled receptor (Lgr) family has been implicated in intestinal, gastric, and epidermal stem cell functions. We investigated whether Lgr4 functions in mammary gland development and mammary stem cells. We found that Lgr4(-/-) mice had delayed ductal development, fewer terminal end buds, and decreased side-branching. Crucially, the mammary stem cell repopulation capacity was severely impaired. Mammospheres from Lgr4(-/-) mice showed decreased Wnt signaling. Wnt3a treatment prevented the adverse effects of Lgr4 loss on organoid formation. Chromatin immunoprecipitation analysis indicated that Sox2 expression was controlled by the Lgr4/Wnt/β-catenin/Lef1 pathway. Importantly, Sox2 overexpression restored the in vivo mammary regeneration potential of Lgr4(-/-) mammary stem cells. Therefore, Lgr4 activates Sox2 to regulate mammary development and stem cell functions via Wnt/β-catenin/Lef1.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Lai
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D039902:Multipotent Stem Cells / Q000166:cytology; D009940:Organoids / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D012038:Regeneration; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse
keywords: Gpr48; Lgr4; Mammary stem cell; Sox2; Wnt signaling