Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis.
During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.
Wiseman
Bryony S
BS
Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Sternlicht
Mark D
MD
Lund
Leif R
LR
Alexander
Caroline M
CM
Mott
Joni
J
Bissell
Mina J
MJ
Soloway
Paul
P
Itohara
Shigeyoshi
S
Werb
Zena
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D004151:Dipeptides / Q000494:pharmacology; D004627:Embryonic Induction / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D007150:Immunohistochemistry; D007774:Lactation / Q000187:drug effects / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009924:Organ Culture Techniques; D011247:Pregnancy; D011480:Protease Inhibitors / Q000494:pharmacology; D012741:Sexual Maturation / Q000187:drug effects / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D004151:Dipeptides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2