Molecular Endocrinology, Vol 10, 903-918, Copyright © 1996 by Endocrine Society

ARTICLES

Effects of an Igf1 gene null mutation on mouse reproduction

J Baker, MP Hardy, J Zhou, C Bondy, F Lupu, AR Bellve and A Efstratiadis
Department of Genetics and Development, Columbia University, New York, New York 10032, USA.

Both sexes of adult mice homozygous for a targeted mutation of the Igf1 gene, encoding insulin-like growth factor 1, are infertile dwarfs (approximately 30% of normal size). The testes are reduced in size less than expected from the degree of dwarfism but sustain spermatogenesis only at 18% of the normal level. The epididymides are overall nearly allometric to the reduced body weight, but the distal regions of the duct, vas deferens, seminal vesicles, and prostate are vestigial. Despite the mutational impact on the epididymis, capacitated sperm are able to fertilize wild type eggs in vitro. It is hypothesized that the infertility of male mutants is caused by failure of androgenization resulting in absence of mating behavior, due to drastically reduced levels of serum testosterone (18% of normal). This hormonal deficiency was correlated with an ultrastructural analysis of mutant Leydig cells revealing a significant developmental delay, while assays in organ culture showed that the basal and LH-stimulated production of testosterone by testicular parenchyma is reduced in comparison with wild type controls. The female mutants fail to ovulate even after administration of gonadotropins, which is apparently the primary cause of their infertility, and possess an infantile uterus that exhibits a dramatic hypoplasia especially in the myometrium. The phenotypic manifestations of the mutation were correlated with the localization of transcripts for insulin-like growth factor I and its cognate receptor in wild type reproductive tissues by in situ hybridization.

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				K. M. Taylor, C. Chen, C. A. Gray, F. W. Bazer, and T. E. Spencer Expression of Messenger Ribonucleic Acids for Fibroblast Growth Factors 7 and 10, Hepatocyte Growth Factor, and Insulin-Like Growth Factors and Their Receptors in the Neonatal Ovine Uterus Biol Reprod, April 1, 2001; 64(4): 1236 - 1246. [Abstract] [Full Text]

				J. S. Richards New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells Mol. Endocrinol., February 1, 2001; 15(2): 209 - 218. [Abstract] [Full Text]

				B. C. Paria, W.-g. Ma, J. Tan, S. Raja, S. K. Das, S. K. Dey, and B. L. M. Hogan Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors PNAS, January 30, 2001; 98(3): 1047 - 1052. [Abstract] [Full Text] [PDF]

				J. Y. Wu, I. J. Gonzalez-Robayna, J. S. Richards, and A. R. Means Female Fertility Is Reduced in Mice Lacking Ca2+/Calmodulin-Dependent Protein Kinase IV Endocrinology, December 1, 2000; 141(12): 4777 - 4783. [Abstract] [Full Text] [PDF]

				N. Sekar, H. A. LaVoie, and J. D. Veldhuis Concerted Regulation of Steroidogenic Acute Regulatory Gene Expression by Luteinizing Hormone and Insulin (or Insulin-Like Growth Factor I) in Primary Cultures of Porcine Granulosa-Luteal Cells Endocrinology, November 1, 2000; 141(11): 3983 - 3992. [Abstract] [Full Text] [PDF]

				K. Englund, B. Lindblom, K. Carlstrom, I. Gustavsson, P. Sjoblom, and A. Blanck Gene expression and tissue concentrations of IGF-I in human myometrium and fibroids under different hormonal conditions Mol. Hum. Reprod., October 1, 2000; 6(10): 915 - 920. [Abstract] [Full Text] [PDF]

				T. L. Wood, L. E. Rogler, M. E. Czick, A. G.P. Schuller, and J. E. Pintar Selective Alterations in Organ Sizes in Mice with a Targeted Disruption of the Insulin-Like Growth Factor Binding Protein-2 Gene Mol. Endocrinol., September 1, 2000; 14(9): 1472 - 1482. [Abstract] [Full Text]

				H. Louhio, O. Hovatta, J. Sjoberg, and T. Tuuri The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture Mol. Hum. Reprod., August 1, 2000; 6(8): 694 - 698. [Abstract] [Full Text] [PDF]

				S.-A. Wandji, J. E. Gadsby, F. A. Simmen, J. A. Barber, and J. M. Hammond Porcine Ovarian Cells Express Messenger Ribonucleic Acids for the Acid-Labile Subunit and Insulin-Like Growth Factor Binding Protein-3 during Follicular and Luteal Phases of the Estrous Cycle Endocrinology, July 1, 2000; 141(7): 2638 - 2647. [Abstract] [Full Text] [PDF]

				E. R. Hernandez Embryo implantation and GnRH antagonists: Embryo implantation: the Rubicon for GnRH antagonists Hum. Reprod., June 1, 2000; 15(6): 1211 - 1216. [Abstract] [Full Text] [PDF]

				L. Gnessi, S. Basciani, S. Mariani, M. Arizzi, G. Spera, C. Wang, C. Bondjers, L. Karlsson, and C. Betsholtz Leydig Cell Loss and Spermatogenic Arrest in Platelet-Derived Growth Factor (Pdgf)-a-Deficient Mice J. Cell Biol., May 29, 2000; 149(5): 1019 - 1026. [Abstract] [Full Text] [PDF]

				M. J. Bouchard, Y. Dong, B. M. McDermott Jr., D.-H. Lam, K. R. Brown, M. Shelanski, A. R. Bellvé, and V. R. Racaniello Defects in Nuclear and Cytoskeletal Morphology and Mitochondrial Localization in Spermatozoa of Mice Lacking Nectin-2, a Component of Cell-Cell Adherens Junctions Mol. Cell. Biol., April 15, 2000; 20(8): 2865 - 2873. [Abstract] [Full Text]

				E. A. McGee and A. J. W. Hsueh Initial and Cyclic Recruitment of Ovarian Follicles Endocr. Rev., April 1, 2000; 21(2): 200 - 214. [Abstract] [Full Text]

				J.-L. Liu, S. Yakar, and D. LeRoith Conditional Knockout of Mouse Insulin-Like Growth Factor-1 Gene Using the Cre/loxP System Experimental Biology and Medicine, April 1, 2000; 223(4): 344 - 351. [Abstract] [Full Text] [PDF]

				T. Minegishi, T. Hirakawa, H. Kishi, K. Abe, Y. Abe, T. Mizutani, and K. Miyamoto A Role of Insulin-Like Growth Factor I for Follicle-Stimulating Hormone Receptor Expression in Rat Granulosa Cells Biol Reprod, February 1, 2000; 62(2): 325 - 333. [Abstract] [Full Text]

				N. A. Danilovich, A. Bartke, and T. A. Winters Ovarian Follicle Apoptosis in Bovine Growth Hormone Transgenic Mice Biol Reprod, January 1, 2000; 62(1): 103 - 107. [Abstract] [Full Text]

				A. Bartke, V. Chandrashekar, D. Turyn, R. W. Steger, L. Debeljuk, T. A. Winters, J. A. Mattison, N. A. Danilovich, W. Croson, D. R. Wernsing, et al. Effects of Growth Hormone Overexpression and Growth Hormone Resistance on Neuroendocrine and Reproductive Functions in Transgenic and Knock-Out Mice Experimental Biology and Medicine, November 1, 1999; 222(2): 113 - 123. [Abstract] [Full Text]

				T. Hirakawa, T. Minegishi, K. Abe, H. Kishi, Y. Ibuki, and K. Miyamoto A Role of Insulin-Like Growth Factor I in Luteinizing Hormone Receptor Expression in Granulosa Cells Endocrinology, November 1, 1999; 140(11): 4965 - 4971. [Abstract] [Full Text]