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Published 15 September 2003. doi:10.1083/jcb.200302090
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© The Rockefeller University Press, 0021-9525/2003/9/1123 $5.00
The Journal of Cell Biology, Volume 162, Number 6, 1123-1133

Article

Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis



Bryony S. Wiseman1, Mark D. Sternlicht1, Leif R. Lund2, Caroline M. Alexander1, Joni Mott3, Mina J. Bissell3, Paul Soloway4, Shigeyoshi Itohara5 and Zena Werb1

1 Department of Anatomy, University of California, San Francisco, CA 94143
2 The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark
3 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
4 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853
5 Laboratory of Behavioral Genetics, Brain Science Institute, Institute of Physical and Chemical Research, 2-1 Hirosawa, Wako 351-0198, Japan

Address correspondence to Zena Werb, Dept. of Anatomy, HSW 1320/1321, University of California, 513 Parnassus Ave., San Francisco, CA 94143-0452. Tel.: (415) 476-4622. Fax: (415) 476-4565. email: zena{at}itsa.ucsf.edu

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.

Key Words: apoptosis; matrix metalloproteinases; stromal–epithelial interaction; terminal end bud; tissue inhibitor of metalloproteinases

Caroline M. Alexander's present address is McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706-1599.

Abbreviations used in this paper: BM, basement membrane; Ln, laminin; MMP, matrix metalloproteinase; TEB, terminal end bud; TIMP, tissue inhibitor of metalloproteinases.


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