Targeted expression of des(1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression.
To test the hypothesis that insulin-like growth factor I (IGF-I) regulates mammary gland development and lactation, the expression of both human (h) IGF-I and des(1-3)hIGF-I was targeted to the mammary gland in transgenic mice using a novel exon replacement strategy and the rat whey acidic protein (rWAP) gene regulatory sequences. Both transgenes expressed a 0.7-kilobase messenger RNA (mRNA). The abundance of WAP-IGE-I and WAP-DES mRNA on day 10 of lactation ranged from 0.2-1.0% and 0.2-13% of the endogenous mouse WAP mRNA, respectively. For WAP-DES mice, transgene expression was greatest from midpregnancy throughout lactation. Western blot analysis showed the presence of correctly processed hIGF-I in milk from these transgenic mice. This hIGF-I was capable of stimulating protein synthesis in cultured rat L6 myoblasts. Ligand blotting indicated changes in mammary gland secretion of IGFBP in response to WAP-DES expression. Histological analysis of mammary tissue from mice overexpressing des(1-3)hIGF-I showed incomplete mammary involution, ductile hypertrophy, and loss of secretory lobules associated with increased deposition of collagen. These changes are believed to occur through autocrine and paracrine effects of des(1-3)-hIGF-I on both epithelial and stromal cells.
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
D L
DL
Hadsell
N M
NM
Greenberg
J M
JM
Fligger
C R
CR
Baumrucker
J M
JM
Rosen
D000818:Animals; D001483:Base Sequence; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007774:Lactation; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D008894:Milk Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution
D018969:Insulin-Like Growth Factor Binding Proteins; D008894:Milk Proteins; D015345:Oligonucleotide Probes; D010446:Peptide Fragments; D012333:RNA, Messenger; C024471:whey acidic proteins; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I