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

Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ, Soloway P, Itohara S, Werb Z - J. Cell Biol. (2003)

Bottom Line: 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.Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Localization of MMPs-2, -3, -9, and -14 mRNA within the mammary gland. Mammary glands were taken at 50 d old and sectioned. (A–C, K, and O) Hematoxylin and eosin counterstain of mammary gland sections in G–J and N, respectively. Note the initiating lateral branch in A (black arrow) and TEB in B (black outlined arrow). In situ hybridization analysis was performed with the following antisense and sense probes (as indicated): (D–F) MMP-2, (G–I) MMP-14, (J, L, and M) MMP-9, and (N, P, and Q) MMP-3. Note the reduction in MMP-2, but not MMP-14 mRNA, at the initiating lateral branch in the adjacent sections D and G (white outlined arrows); the localization of MMP-14 around the TEB in H (white arrow) and the spots of MMP-9 expression probably localized in macrophages in L (white arrow heads). Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172848&req=5

fig1: Localization of MMPs-2, -3, -9, and -14 mRNA within the mammary gland. Mammary glands were taken at 50 d old and sectioned. (A–C, K, and O) Hematoxylin and eosin counterstain of mammary gland sections in G–J and N, respectively. Note the initiating lateral branch in A (black arrow) and TEB in B (black outlined arrow). In situ hybridization analysis was performed with the following antisense and sense probes (as indicated): (D–F) MMP-2, (G–I) MMP-14, (J, L, and M) MMP-9, and (N, P, and Q) MMP-3. Note the reduction in MMP-2, but not MMP-14 mRNA, at the initiating lateral branch in the adjacent sections D and G (white outlined arrows); the localization of MMP-14 around the TEB in H (white arrow) and the spots of MMP-9 expression probably localized in macrophages in L (white arrow heads). Bars, 50 μm.

Mentions: First, we determined where MMPs were expressed in the mammary gland by in situ hybridization on sections of pubertal mouse mammary tissue (Fig. 1). Four MMPs were expressed in distinct locations in the mammary gland during puberty. MMP-2 mRNA was concentrated primarily in the periductal stroma and was weakly expressed by adipose tissue. Surprisingly, its expression was reduced at sites of initiating buds or side branches (Fig. 1 D). The mRNA for MMP-14, the principal activator of MMP-2, (Will et al., 1996) overlapped MMP-2 expression only in part. MMP-14 was mainly stromal, but also present in the epithelium, with no reduction at branch initiation sites; instead it was highly concentrated within and around TEBs. MMP-3 was exclusively stromal and located in periductal stroma and the adipose tissue, with no difference at sites of initiating branches. MMP-9 was expressed at low levels throughout the gland in the epithelium and the stroma. There were spots of concentrated MMP-9 (gelatinase B) mRNA that correspond to macrophages.


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

Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ, Soloway P, Itohara S, Werb Z - J. Cell Biol. (2003)

Localization of MMPs-2, -3, -9, and -14 mRNA within the mammary gland. Mammary glands were taken at 50 d old and sectioned. (A–C, K, and O) Hematoxylin and eosin counterstain of mammary gland sections in G–J and N, respectively. Note the initiating lateral branch in A (black arrow) and TEB in B (black outlined arrow). In situ hybridization analysis was performed with the following antisense and sense probes (as indicated): (D–F) MMP-2, (G–I) MMP-14, (J, L, and M) MMP-9, and (N, P, and Q) MMP-3. Note the reduction in MMP-2, but not MMP-14 mRNA, at the initiating lateral branch in the adjacent sections D and G (white outlined arrows); the localization of MMP-14 around the TEB in H (white arrow) and the spots of MMP-9 expression probably localized in macrophages in L (white arrow heads). Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172848&req=5

fig1: Localization of MMPs-2, -3, -9, and -14 mRNA within the mammary gland. Mammary glands were taken at 50 d old and sectioned. (A–C, K, and O) Hematoxylin and eosin counterstain of mammary gland sections in G–J and N, respectively. Note the initiating lateral branch in A (black arrow) and TEB in B (black outlined arrow). In situ hybridization analysis was performed with the following antisense and sense probes (as indicated): (D–F) MMP-2, (G–I) MMP-14, (J, L, and M) MMP-9, and (N, P, and Q) MMP-3. Note the reduction in MMP-2, but not MMP-14 mRNA, at the initiating lateral branch in the adjacent sections D and G (white outlined arrows); the localization of MMP-14 around the TEB in H (white arrow) and the spots of MMP-9 expression probably localized in macrophages in L (white arrow heads). Bars, 50 μm.
Mentions: First, we determined where MMPs were expressed in the mammary gland by in situ hybridization on sections of pubertal mouse mammary tissue (Fig. 1). Four MMPs were expressed in distinct locations in the mammary gland during puberty. MMP-2 mRNA was concentrated primarily in the periductal stroma and was weakly expressed by adipose tissue. Surprisingly, its expression was reduced at sites of initiating buds or side branches (Fig. 1 D). The mRNA for MMP-14, the principal activator of MMP-2, (Will et al., 1996) overlapped MMP-2 expression only in part. MMP-14 was mainly stromal, but also present in the epithelium, with no reduction at branch initiation sites; instead it was highly concentrated within and around TEBs. MMP-3 was exclusively stromal and located in periductal stroma and the adipose tissue, with no difference at sites of initiating branches. MMP-9 was expressed at low levels throughout the gland in the epithelium and the stroma. There were spots of concentrated MMP-9 (gelatinase B) mRNA that correspond to macrophages.

Bottom Line: 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.Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus