Analysis of gene expression in PTHrP-/- mammary buds supports a role for BMP signaling and MMP2 in the initiation of ductal morphogenesis.
Parathyroid hormone-related protein (PTHrP) acts on the mammary mesenchyme and is required for proper embryonic mammary development. In order to understand PTHrP's effects on mesenchymal cells, we profiled gene expression in WT and PTHrP(-/-) mammary buds, and in WT and K14-PTHrP ventral skin at E15.5. By cross-referencing the differences in gene expression between these groups, we identified 35 genes potentially regulated by PTHrP in the mammary mesenchyme, including 6 genes known to be involved in BMP signaling. One of these genes was MMP2. We demonstrated that PTHrP and BMP4 regulate MMP2 gene expression and MMP2 activity in mesenchymal cells. Using mammary bud cultures, we demonstrated that MMP2 acts downstream of PTHrP to stimulate ductal outgrowth. Future studies on the functional role of other genes on this list should expand our knowledge of how PTHrP signaling triggers the onset of ductal outgrowth from the embryonic mammary buds.
Department of Biology, St. Bonaventure University, St. Bonaventure, New York, USA.
Julie
J
Hens
Pamela
P
Dann
Minoti
M
Hiremath
Tien-Chi
TC
Pan
Lewis
L
Chodosh
John
J
Wysolmerski
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D004151:Dipeptides; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D044162:Parathyroid Hormone-Related Protein; D011480:Protease Inhibitors; D014157:Transcription Factors; C474031:N-hydroxy-9-octadecenamide; D007633:Keratins; D020778:Matrix Metalloproteinase 2