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This version published online on January 28, 2004
Endocrinology, doi:10.1210/en.2003-1196
A more recent version of this article appeared on May 1, 2004
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Submitted on September 9, 2003
Accepted on January 21, 2004

IGFBP-6 transgenic mice: post-natal growth, brain development and reproduction abnormalities

Géraldine Bienvenu, Danielle Seurin, Pascale Grellier, Pascal Froment, Marielle Baudrimont, Philippe Monget, Yves Le Bouc, and Sylvie Babajko*

Unité de Recherche INSERM 515 : Croissance, Différenciation et Processus tumoraux, Institut National de la Santé et de la Recherche Médicale, Hôpital Saint Antoine, 75571 Paris Cedex 12, France; Physiologie de la Reproduction et des Comportements, UMR 6073 INRA-CNRS-Université de Tours, 37380 Nouzilly, France; Service d'Anatomo-Pathologie, Hôpital Sainte Anne, 75014 Paris, France

* To whom correspondence should be addressed. E-mail: U515{at}st-antoine.inserm.fr.

In biological fluids, IGFs bind to six distinct binding proteins (IGFBP-1 to -6). IGFBP-6 is of particular interest, since 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 (h) IGFBP-6 cDNA is expressed under the control of the 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 one month of age, transgenic mice had high levels of circulating hIGFBP-6 and reduced plasma IGF-I, as a result of which 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 a useful tool in elucidating the in vivo role of IGFBP-6 in the brain, especially as regards hypothalamic control, and in reproductive physiology.
Key words: IGF system • IGFBP-6 • transgenic mice • reproduction • ovary • cerebellum • GFAP




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