help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gay, E.
Right arrow Articles by Binoux, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gay, E.
Right arrow Articles by Binoux, M.
Endocrinology Vol. 138, No. 7 2937-2947
Copyright © 1997 by The Endocrine Society

ARTICLES

Liver-Specific Expression of Human Insulin-Like Growth Factor Binding Protein-1 in Transgenic Mice: Repercussions on Reproduction, Ante- and Perinatal Mortality and Postnatal Growth1

Emmanuel Gay, Danielle Seurin, Sylvie Babajko, Sophie Doublier, Michéle Cazillis and Michel Binoux

Institut National de la Santé et de la Recherche Médicale, Unité de Recherches sur la Régulation de la Croissance, Hôpital Saint Antoine, Paris 75571, France

Address all correspondence and requests for reprints to: M. Binoux, INSERM Unité 142, Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571 Paris Cedex 12, France.

Study of the in vivo functions of the insulin-like growth factor binding proteins (IGFBPs) is complicated by their variety (six molecular species) and the differences in their expression related to tissue of origin and stage of development. To investigate the physiological role of IGFBP-1 in the bloodstream, we induced hepatic overexpression of IGFBP-1 in transgenic mice, placing human IGFBP-1 (hIGFBP-1) cDNA under the control of the {alpha}1-antitrypsin promoter so as to obtain liver-specific expression.

Five transgenic founder mice were raised, only two of which (lines 124 and 149) produced transgenic offspring. Northern blotting revealed transgene expression exclusively in the liver during fetal life and unchanged through to adulthood, whereas expression of the endogenous gene was undetectable beyond 10–15 days postnatally. hIGFBP-1 was detected by western immunoblotting in the plasma of transgenic mice and IRMAs yielded mean concentrations of 2.41 ± 0.33 ng/ml and 13.69 ± 1.42 ng/ml in homozygous animals of lines 124 and 149, respectively. In the latter, IGFBP-1 levels were distinctly higher than in heterozygotes (2.99 ± 0.39 ng/ml), P < 0.0001. These levels remained stable in each given animal and did not change with age. Plasma concentrations of IGF-I measured in line 149 exhibited the well-known profile of an increase from birth up to puberty. Values for heterozygotes were similar to those for wild-type mice, with adult levels (544 ± 98 ng/ml) slightly below those of controls (630 ± 56 ng/ml), P < 0.05. In homozygotes they were distinctly lower, with adult levels of 370 ± 75 ng/ml, P = 0.001. In heterozygous and homozygous adults, there was a negative correlation between IGF-I and IGFBP-1 concentrations (r = 0.8, P < 0.0001), suggesting a link between transgene expression and IGF-I levels.

Study of body weight gain in line 149 revealed growth retardation within the first weeks after birth, which was marked in homozygous males and females (P < 0.001) but also present in heterozygous males (P = 0.002), indicating some relationship with transgene expression. In addition, body weight in adult mice was negatively correlated to plasma concentrations of IGFBP-1 (r = 0.7, P < 0.0001).

Reproductive function also appeared to be severely affected, especially in homozygous females: mating that failed to result in pregnancy in half of the homozygous females crossed with nontransgenic males, suggestive of impaired fertilization or implantation; interrupted or prolonged pregnancies with fetal and neonatal death. Litter size was reduced in transgenic females (by about half in homozygotes) and in nontransgenic females mated with homozygous males, resulting from pre- or neonatal mortality. Moreover, deaths occurred within the first 5 days of life, with an incidence of approximately 50% in the litters of homozygous females, 12–18% among heterozygotes mated with nontransgenic or heterozygous males, respectively, and 30% among those mated with homozygous males. These results, suggesting that fetal transgene expression largely accounted for ante- and perinatal mortality, were confirmed by the predominance of homozygotes among those that could be analyzed genetically. Similarly impaired reproductive function was seen in line 124, but to a lesser degree.

Although the mechanisms responsible for these disorders remain to be determined, our results indicate that permanent and uncontrolled hepatic expression of IGFBP-1, even at low levels, affects fertility in females and both ante- and postnatal development.




This article has been cited by other articles:


Home page
 EndocrinologyHome page
Y. Zha, V. T. Le, Y. Higami, I. Shimokawa, T. Taguchi, and M. S. Razzaque
Life-Long Suppression of Growth Hormone-Insulin-Like Growth Factor I Activity in Genetically Altered Rats Could Prevent Age-Related Renal Damage
Endocrinology, December 1, 2006; 147(12): 5690 - 5698.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
V. Shukla, X. Coumoul, L. Cao, R.-H. Wang, C. Xiao, X. Xu, S. Ando, S. Yakar, D. LeRoith, and C. Deng
Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members.
Cancer Res., July 15, 2006; 66(14): 7151 - 7157.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Marchand, C. Tomkiewicz, L. Magne, R. Barouki, and M. Garlatti
Endoplasmic Reticulum Stress Induction of Insulin-like Growth Factor-binding Protein-1 Involves ATF4
J. Biol. Chem., July 14, 2006; 281(28): 19124 - 19133.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. S. Watson, P. Bialek, M. Anzo, J. Khosravi, S.-P. Yee, and V. K. M. Han
Elevated Circulating Insulin-Like Growth Factor Binding Protein-1 Is Sufficient to Cause Fetal Growth Restriction
Endocrinology, March 1, 2006; 147(3): 1175 - 1186.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. Kajimura, K. Aida, and C. Duan
Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression
Mol. Cell. Biol., February 1, 2006; 26(3): 1142 - 1155.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Stefan, H. Ji, R. A. Simmons, D. E. Cummings, R. S. Ahima, M. I. Friedman, and R. D. Nicholls
Hormonal and Metabolic Defects in a Prader-Willi Syndrome Mouse Model with Neonatal Failure to Thrive
Endocrinology, October 1, 2005; 146(10): 4377 - 4385.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. Marchand, C. Tomkiewicz, J.-P. Marchandeau, E. Boitier, R. Barouki, and M. Garlatti
2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Insulin-Like Growth Factor Binding Protein-1 Gene Expression and Counteracts the Negative Effect of Insulin
Mol. Pharmacol., February 1, 2005; 67(2): 444 - 452.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Kajimura, K. Aida, and C. Duan
From the Cover: Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation
PNAS, January 25, 2005; 102(4): 1240 - 1245.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
V. Cingel-Ristic, J. W. van Neck, J. Frystyk, S. L. S. Drop, and A. Flyvbjerg
Administration of Human Insulin-Like Growth Factor-Binding Protein-1 Increases Circulating Levels of Growth Hormone in Mice
Endocrinology, September 1, 2004; 145(9): 4401 - 4407.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
V. Chandrashekar, D. Zaczek, and A. Bartke
The Consequences of Altered Somatotropic System on Reproduction
Biol Reprod, July 1, 2004; 71(1): 17 - 27.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. Froment, C. Staub, S. Hembert, C. Pisselet, M. Magistrini, B. Delaleu, D. Seurin, J. E. Levine, L. Johnson, M. Binoux, et al.
Reproductive Abnormalities in Human Insulin-Like Growth Factor-Binding Protein-1 Transgenic Male Mice
Endocrinology, April 1, 2004; 145(4): 2080 - 2091.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
S. B. Wheatcroft, M. T. Kearney, A. M. Shah, D. J. Grieve, I. L. Williams, J. P. Miell, and P. A. Crossey
Vascular Endothelial Function and Blood Pressure Homeostasis in Mice Overexpressing IGF Binding Protein-1
Diabetes, August 1, 2003; 52(8): 2075 - 2082.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
S. M. Firth and R. C. Baxter
Cellular Actions of the Insulin-Like Growth Factor Binding Proteins
Endocr. Rev., December 1, 2002; 23(6): 824 - 854.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. V. Silha and L. J. Murphy
Minireview: Insights from Insulin-Like Growth Factor Binding Protein Transgenic Mice
Endocrinology, October 1, 2002; 143(10): 3711 - 3714.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
I. Foucher, M. Volovitch, M. Frain, J. J. Kim, J.-C. Souberbielle, L. Gan, T. G. Unterman, A. Prochiantz, and A. Trembleau
Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors
Development, September 1, 2002; 129(17): 4065 - 4074.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
P. Chavatte-Palmer, Y. Heyman, C. Richard, P. Monget, D. LeBourhis, G. Kann, Y. Chilliard, X. Vignon, and J.P. Renard
Clinical, Hormonal, and Hematologic Characteristics of Bovine Calves Derived from Nuclei from Somatic Cells
Biol Reprod, June 1, 2002; 66(6): 1596 - 1603.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. Froment, D. Seurin, S. Hembert, J. E. Levine, C. Pisselet, D. Monniaux, M. Binoux, and P. Monget
Reproductive Abnormalities in Human IGF Binding Protein-1 Transgenic Female Mice
Endocrinology, May 1, 2002; 143(5): 1801 - 1808.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Holzenberger, G. Hamard, R. Zaoui, P. Leneuve, B. Ducos, C. Beccavin, L. Perin, and Y. Le Bouc
Experimental IGF-I Receptor Deficiency Generates a Sexually Dimorphic Pattern of Organ-Specific Growth Deficits in Mice, Affecting Fat Tissue in Particular
Endocrinology, October 1, 2001; 142(10): 4469 - 4478.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
E. Baixeras, S. Jeay, P. A. Kelly, and M.-C. Postel-Vinay
The Proliferative and Antiapoptotic Actions of Growth Hormone and Insulin-Like Growth Factor-1 Are Mediated through Distinct Signaling Pathways in the Pro-B Ba/F3 Cell Line
Endocrinology, July 1, 2001; 142(7): 2968 - 2977.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. T. Wiekowski, M. W. Leach, E. W. Evans, L. Sullivan, S.-C. Chen, G. Vassileva, J. F. Bazan, D. M. Gorman, R. A. Kastelein, S. Narula, et al.
Ubiquitous Transgenic Expression of the IL-23 Subunit p19 Induces Multiorgan Inflammation, Runting, Infertility, and Premature Death
J. Immunol., June 15, 2001; 166(12): 7563 - 7570.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. Lassarre, F. Duron, and M. Binoux
Use of the Ligand Immunofunctional Assay for Human Insulin-Like Growth Factor (IGF) Binding Protein-3 (IGFBP-3) to Analyze IGFBP-3 Proteolysis and IGF-I Bioavailability in Healthy Adults, GH-Deficient and Acromegalic Patients, and Diabetics
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1942 - 1952.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
A. Hoeflich, S. Nedbal, W. F. Blum, M. Erhard, H. Lahm, G. Brem, H. J. Kolb, R. Wanke, and E. Wolf
Growth Inhibition in Giant Growth Hormone Transgenic Mice by Overexpression of Insulin-Like Growth Factor-Binding Protein-2
Endocrinology, May 1, 2001; 142(5): 1889 - 1898.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
C. LASSARRE and M. BINOUX
Measurement of Intact Insulin-Like Growth Factor-Binding Protein-3 in Human Plasma Using a Ligand Immunofunctional Assay
J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1260 - 1266.
[Abstract] [Full Text]

Home page
 Mol. Cell. Biol.Home page
F. M. Rausa, Y. Tan, H. Zhou, K. W. Yoo, D. B. Stolz, S. C. Watkins, R. R. Franks, T. G. Unterman, and R. H. Costa
Elevated Levels of Hepatocyte Nuclear Factor 3beta in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis
Mol. Cell. Biol., November 1, 2000; 20(21): 8264 - 8282.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
A. Logie, P. Boudou, L. Boccon-Gibod, E. Baudin, G. Vassal, M. Schlumberger, Y. Le Bouc, and C. Gicquel
Establishment and Characterization of a Human Adrenocortical Carcinoma Xenograft Model
Endocrinology, September 1, 2000; 141(9): 3165 - 3171.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Holzenberger, P. Leneuve, G. Hamard, B. Ducos, L. Perin, M. Binoux, and Y. Le Bouc
A Targeted Partial Invalidation of the Insulin-Like Growth Factor I Receptor Gene in Mice Causes a Postnatal Growth Deficit
Endocrinology, July 1, 2000; 141(7): 2557 - 2566.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. C. van Buul-Offers, M. van Kleffens, J. G. Koster, D. J. Lindenbergh-Kortleve, M. G. Gresnigt, S. L. S. Drop, C. M. Hoogerbrugge, R. J. Bloemen, J. A. Koedam, and J. W. van Neck
Human Insulin-Like Growth Factor (IGF) Binding Protein-1 Inhibits IGF-I-Stimulated Body Growth but Stimulates Growth of the Kidney in Snell Dwarf Mice
Endocrinology, April 1, 2000; 141(4): 1493 - 1499.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
M. R. SCHNEIDER, H. LAHM, M. WU, A. HOEFLICH, and E. WOLF
Transgenic mouse models for studying the functions of insulin-like growth factor-binding proteins
FASEB J, April 1, 2000; 14(5): 629 - 640.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
A. Hoeflich, M. Wu, S. Mohan, J. Föll, R. Wanke, T. Froehlich, G. J. Arnold, H. Lahm, H. J. Kolb, and E. Wolf
Overexpression of Insulin-Like Growth Factor-Binding Protein-2 in Transgenic Mice Reduces Postnatal Body Weight Gain
Endocrinology, December 1, 1999; 140(12): 5488 - 5496.
[Abstract] [Full Text]

Home page
 Hum ReprodHome page
D. Fowler, G. Albaiges, C. Lees, J. Jones, K. Nicolaides, and J. Miell
The role of insulin-like growth factor binding protein-1 phosphoisoforms in pregnancies with impaired placental function identified by Doppler ultrasound
Hum. Reprod., November 1, 1999; 14(11): 2881 - 2885.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. R. Powell, S. K. Durham, E. D. Brewer, J. W. Frane, S. L. Watkins, R. J. Hogg, and S. Mohan
Effects of Chronic Renal Failure and Growth Hormone on Serum Levels of Insulin-Like Growth Factor-Binding Protein-4 (IGFBP-4) and IGFBP-5 in Children: A Report of the Southwest Pediatric Nephrology Study Group
J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 596 - 601.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. E. Wilson
Effects of Estradiol and Exogenous Insulin-Like Growth Factor I (IGF-I) on the IGF-I Axis during Growth Hormone Inhibition and Antagonism
J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 4013 - 4021.
[Abstract] [Full Text]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
V. Besnard, E. Nabeyrat, A. Henrion-Caude, K. Chadelat, L. Perin, Y. Le Bouc, and A. Clement
Protective role of retinoic acid from antiproliferative action of TNF-alpha on lung epithelial cells
Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L863 - L871.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1997 by The Endocrine Society