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, MT1-MMP/MMP14 and MT2-MMP/MMP15, that 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. Herein, we characterize the impact of global Mmp14 and Mmp15 targeting on early postnatal mammary gland development. Unexpectedly, both Mmp14−/- and Mmp15−/- mammary glands retain the ability to generate intact ductal networks. Though 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 critical 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.