title: Insulin-like growth factor binding protein-6 transgenic mice: postnatal growth, brain development, and reproduction abnormalities.
abstract: In biological fluids, IGFs bind to six distinct binding proteins (IGFBP-1 to -6). IGFBP-6 is of particular interest because it has been shown to inhibit proliferation in many cell types and to be synthesized in the central nervous system (CNS). It also has the strongest affinity for IGF-II among the IGFBPs. To study IGFBP-6 function in vivo, we established IGFBP-6 transgenic mice in which human IGFBP-6 (hIGFBP-6) cDNA is expressed under the control of the glial fibrillary acidic protein (GFAP) promoter. Northern and Western blot analysis revealed strong transgene expression in the CNS. With histological examination of the CNS, cerebellum size and weight proved to be reduced by about 25% and 35%, respectively, and there were smaller numbers of differentiated, GFAP-expressing astrocytes than in wild-type mice. Between birth and 1 month of age, transgenic mice had high levels of circulating hIGFBP-6 and reduced plasma IGF-I, and, as a result, body weight was significantly reduced. Reproductive physiology was also affected. Litter size was reduced by 27% when wild-type males were mated with 3-month-old transgenic females and by 66% when mated with 6-month-old transgenic females. Histological examination of ovaries of transgenic mice revealed a marked decrease in weight and in the number of corpora lutea, suggesting altered ovulation, and circulating LH levels were reduced by 50%. Our results indicate that this new model of transgenic mouse may prove to be a useful tool in elucidating the in vivo role of IGFBP-6 in the brain, especially in regard to hypothalamic control, and in reproductive physiology.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 515, Hôpital Saint Antoine, 184 rue du Faubourg St. Antoine, 75571 Paris Cedex 12, France. U515@st-antoine.inserm.fr.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Bienvenu
authors.forename: Danielle
authors.initials: D
authors.lastname: Seurin
authors.forename: Pascale
authors.initials: P
authors.lastname: Grellier
authors.forename: Pascal
authors.initials: P
authors.lastname: Froment
authors.forename: Marielle
authors.initials: M
authors.lastname: Baudrimont
authors.forename: Philippe
authors.initials: P
authors.lastname: Monget
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.forename: Sylvie
authors.initials: S
authors.lastname: Babajko
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000737:chemistry; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000254:growth & development*; D002531:Cerebellum / Q000033:anatomy & histology; D005260:Female; D005313:Fetal Death; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006128:Growth; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics* / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008098:Litter Size; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009929:Organ Size; D010053:Ovary / Q000033:anatomy & histology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012098:Reproduction
chemical_list: D005904:Glial Fibrillary Acidic Protein; D018976:Insulin-Like Growth Factor Binding Protein 6; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone