Peroxisome proliferator-activated receptor alpha activation during pregnancy severely impairs mammary lobuloalveolar development in mice.
To identify the potential functions of peroxisome proliferator-activated receptor alpha (PPARalpha) in skin development, transgenic mice were generated to target constitutively activated PPARalpha (VP16PPARalpha) to the stratified epithelia by use of the keratin K5 promoter. In addition to marked alterations in epidermal development, the transgenic mice had a severe defect in lactation during pregnancy resulting in 100% pup mortality. In this study, the alteration of mammary gland development in these transgenic mice was investigated. The results showed that expression of the VP16PPARalpha transgene during pregnancy resulted in impaired development of lobuloalveoli, which is associated with reduced proliferation and increased apoptosis of mammary epithelia. Mammary epithelia from transgenic mice also showed a significant reduction in the expression of beta-catenin and a down-regulation of one of its target genes, cyclin D1, which is thought to be required for lobuloalveolar development. Furthermore, upon PPARalpha ligand treatment, similar effects on lobuloalveolar development were observed in wild-type mice, but not in PPARalpha-null mice. These findings suggest that PPARalpha activation has a marked influence in mammary lobuloalveolar development.
Yang
Qian
Q
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kurotani
Reiko
R
Yamada
Atsushi
A
Kimura
Shioko
S
Gonzalez
Frank J
FJ
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation; D004396:Coloring Agents; D019938:Cyclin D1 / Q000096:biosynthesis; D004801:Eosine Yellowish-(YS); D005260:Female; D005456:Fluorescent Dyes; D006416:Hematoxylin; D007150:Immunohistochemistry; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013534:Survival; D051176:beta Catenin / Q000096:biosynthesis
D002364:Caseins; D004396:Coloring Agents; D005456:Fluorescent Dyes; D047493:PPAR alpha; D011743:Pyrimidines; D051176:beta Catenin; D019938:Cyclin D1; C006253:pirinixic acid; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin