Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene.
IGFs (IGF-I and IGF-II) are essential for development, and their bioactivities are tightly regulated by six related IGF-binding proteins (IGFBPs). IGFBP-5 is the most highly conserved binding protein and is expressed in several key developmental lineages as well as in multiple adult tissues including the mammary gland. To explore IGFBP-5 actions in vivo, we produced IGFBP-5 knockout (KO) mice. Whole-body growth, selected organ weights, and body composition were essentially normal in IGFBP-5 KO mice, presumably because of substantial compensation by remaining IGFBP family members. The IGFBP-5 KO mice also exhibited normal mammary gland development and were capable of nursing their pups. We then directly evaluated the proposed role of IGFBP-5 in apoptosis and remodeling of mammary gland during involution. We found that the process of involution after forced weaning was delayed in IGFBP-5 KO mice, with both the appearance of apoptotic cells and the reappearance of adipocytes retarded in mutant mice, compared with controls. We also determined the effects of IGFBP-5 deletion on mammary gland development in pubertal females after ovariectomy and stimulation with estradiol/progesterone. In this paradigm, IGFBP-5 KO mammary glands exhibited enhanced alveolar bud formation consistent with enhanced IGF-I action. These results demonstrate that IGFBP-5, although not essential for normal growth, is required for normal mammary gland involution and can regulate mammary gland morphogenesis in response to hormone stimulation.
Ning
Yun
Y
Department of Neuroscience, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Hoang
Bao
B
Schuller
Alwin G P
AG
Cominski
Tara P
TP
Hsu
Ming-Sing
MS
Wood
Teresa L
TL
Pintar
John E
JE
D000818:Animals; D000833:Animals, Suckling; D001823:Body Composition / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007774:Lactation / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011374:Progesterone / Q000494:pharmacology; D014886:Weaning
D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D011374:Progesterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I