title: Functional roles of MMP14 and MMP15 in early postnatal mammary gland development.
abstract: During late embryogenesis, mammary epithelial cells initiate migration programs that drive ductal invasion into the surrounding adipose-rich mesenchyme. Currently, branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases MMP14 (MT1-MMP) and MMP15 (MT2-MMP), which drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remain undefined. Here, we characterize the impact of global Mmp14 and Mmp15 targeting on early postnatal mammary gland development in mice. Unexpectedly, both Mmp14-/-and Mmp15-/-mammary glands retain the ability to generate intact ductal networks. Although neither proteinase is required for branching morphogenesis, transcriptome profiling reveals a key role for MMP14 and MMP15 in regulating mammary gland adipocyte differentiation. Whereas MMP14 promotes the generation of white fat depots crucial for energy storage, MMP15 differentially controls the formation of thermogenic brown fat. Taken together, these data not only indicate that current paradigms relevant to proteinase-dependent morphogenesis need be revisited, but also identify new roles for the enzymes in regulating adipocyte fate determination in the developing mammary gland.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.|Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tamar Y
authors.initials: TY
authors.lastname: Feinberg
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Transgenic Animal Model Core, Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA sjweiss@umich.edu.|Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.|Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Stephen J
authors.identifier: 0000-0002-1864-6075
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D017667:Adipocytes / Q000502:physiology; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D008321:Mammary Glands, Animal / Q000254:growth & development*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology*; D053517:Matrix Metalloproteinase 15 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D022722:Thermogenesis / Q000235:genetics
chemical_list: C507096:Mmp14 protein, mouse; C507100:Mmp15 protein, mouse; D053517:Matrix Metalloproteinase 15; D053511:Matrix Metalloproteinase 14
keywords: Mammary gland; Matrix metalloproteinases; Morphogenesis; Mouse