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.

Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs

“…Likewise, we have found that the early phases of mammary gland branching morphogenesis occurring between embryonic day 16 and postnatal day 10 proceed independently of MT1-MMP (Feinberg et al, 2016). Largely unappreciated, however, neither the basement membrane nor the interstitial matrix of most organ systems are fully mature at birth or in the early postnatal period when the ECM is dominated by hyaluronic acid and associated proteoglycans (Loganathan et al, 2016).…”

“…S1A-C). Recent studies have, however, demonstrated that mammary epithelial cells also express at least 2 members of the membrane-anchored MMP family, i.e., Mmp14/ MT1-MMP and Mmp15 /MT2-MMP (Feinberg et al, 2016). Indeed, using Mmp14 +/LacZ and Mmp15 +/LacZ knock-in lines, both MT-MMPs are readily detected during morphogenesis (Fig.…”

“…Mmp15 lacZ/+ mice were bred and maintained on a C57BL/6J background or mated onto a FVB/NJ background. Mmp14 +/− mice (Feinberg et al, 2016) were bred with a transgenic mouse line expressing enhanced GFP under the control of a chicken β-actin promoter and mated onto a FVB/NJ background. Mmp3 −/− mice (C57BL/6J background), Mmp13 −/− (C57BL/6J background), and Mmp2 −/− mice (129/SVE background) were genotyped as described (Feinberg et al, 2016).…”

“…Mmp14 +/− mice (Feinberg et al, 2016) were bred with a transgenic mouse line expressing enhanced GFP under the control of a chicken β-actin promoter and mated onto a FVB/NJ background. Mmp3 −/− mice (C57BL/6J background), Mmp13 −/− (C57BL/6J background), and Mmp2 −/− mice (129/SVE background) were genotyped as described (Feinberg et al, 2016). Mmp15 global knockout ( Mmp15 −/− ) mice were generated as described (Feinberg et al, 2016) wherein exons 4 and 5 of the catalytic domain were floxed by loxP sites.…”

New Insights of Mammary Gland During Different Stages of Development

“…In the second phase, cell death is accompanied by upregulation of matrix metalloproteinases (MMPs) which are important in the remodeling of the surrounding stroma, accompanied by adipocyte refilling, influx of macrophages, and active plasma kallikrein formation that regulates adipocyte differentiation and stromal remodeling [51]. The MMPs such as MMP14 and MMP15 regulate adipocyte differentiation with promoting deposition of white fat and brown fat, respectively [52]. Circulating factors regulate this phase and it is observed systemic administration of glucocorticoids [6,53] halts this phase which may act through the maintenance of tight junctions [54].…”