Endocrinology, Vol 135, 1392-1400, Copyright © 1994 by Endocrine Society

ARTICLES

Overexpression of a human transforming growth factor-alpha (TGF alpha) transgene reveals a dual antagonistic role of TGF alpha in female sexual development

YJ Ma, GA Dissen, G Merlino, A Coquelin and SR Ojeda
Division of Neuroscience, Oregon Regional Primate Research Center, Beaverton 97006.

The importance of transforming growth factor-alpha (TGF alpha) in female reproductive development was assessed using transgenic mice bearing a human TGF alpha complementary DNA under the control of a mouse metallothionein-1 promoter (MT1-hTGF alpha). Examination of the brain and ovaries 5 h after a single sc injection of zinc chloride, administered to activate the MT1-hTGF alpha transgene, revealed that prominent sites of human TGF alpha messenger RNA expression within these tissues were the hypothalamus and ovarian follicles, respectively. In vitro experiments showed that acute transgene activation increased hypothalamic release of LH-releasing hormone. In contrast, the ovarian steroidal response to gonadotropins, examined in vitro, was markedly attenuated. Chronic activation of transgene expression by daily administration of zinc chloride delayed the time of first estrus (an index of peripubertal estrogen secretion), but shortened the interval between first estrus and the onset of estrous cyclicity (an index of reproductive competence). Accumulation of small antral follicles, accompanied by thecal hypertrophy and enhanced androgen production, preceded the acquisition of ovulatory capacity. These changes were accompanied by reduced serum LH levels, suggesting that the relative inability of small antral follicles to develop further in TGF alpha-overexpressing mice is at least in part due to inappropriate gonadotropin support. Serum LH levels in these animals may be reduced by an augmented androgen negative feedback signal. Nontransgenic mouse ovaries, placed under the control of a transgenic hypothalamus by heterologous grafting, rapidly ovulated and initiated estrous cyclicity. In contrast, acquisition of reproductive capacity was severely delayed in nontransgenic mice bearing transgenic ovarian grafts. The results indicate that TGF alpha regulates female reproductive development through two opposing mechanisms: within the brain, it facilitates the neuroendocrine activation of the process; at the ovarian level, modulates the stimulatory effect of gonadotropin hormones on follicular growth and steroidogenesis.

This article has been cited by other articles:

				A. A Gratao, M. Dahlhoff, F. Sinowatz, E. Wolf, and M. R Schneider Betacellulin Overexpression in the Mouse Ovary Leads to MAPK3/MAPK1 Hyperactivation and Reduces Litter Size by Impairing Fertilization Biol Reprod, January 1, 2008; 78(1): 43 - 52. [Abstract] [Full Text] [PDF]

				T. Takagi, T. Yamamura, T. Anraku, S. Yasuo, N. Nakao, M. Watanabe, M. Iigo, S. Ebihara, and T. Yoshimura Involvement of Transforming Growth Factor {alpha} in the Photoperiodic Regulation of Reproduction in Birds Endocrinology, June 1, 2007; 148(6): 2788 - 2792. [Abstract] [Full Text] [PDF]

				B. M. Windsor-Engnell, E. Kasuya, M. Mizuno, K. L. Keen, and E. Terasawa An increase in in vivo release of LHRH and precocious puberty by posterior hypothalamic lesions in female rhesus monkeys (Macaca mulatta) Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1000 - E1009. [Abstract] [Full Text] [PDF]

				S. R. Ojeda, A. Lomniczi, C. Mastronardi, S. Heger, C. Roth, A.-S. Parent, V. Matagne, and A. E. Mungenast Minireview: The Neuroendocrine Regulation of Puberty: Is the Time Ripe for a Systems Biology Approach? Endocrinology, March 1, 2006; 147(3): 1166 - 1174. [Abstract] [Full Text] [PDF]

				K. Koshibu, E. T. Ahrens, and P. Levitt Postpubertal Sex Differentiation of Forebrain Structures and Functions Depend on Transforming Growth Factor-{alpha} J. Neurosci., April 13, 2005; 25(15): 3870 - 3880. [Abstract] [Full Text] [PDF]

				V. Prevot, A. Lomniczi, G. Corfas, and S. R. Ojeda erbB-1 and erbB-4 Receptors Act in Concert to Facilitate Female Sexual Development and Mature Reproductive Function Endocrinology, March 1, 2005; 146(3): 1465 - 1472. [Abstract] [Full Text] [PDF]

				B. Li, Z. Yang, J. Hou, A. McCracken, M. A. Jennings, and M. Y. J. Ma Compromised Reproductive Function in Adult Female Mice Selectively Expressing Mutant ErbB-1 Tyrosine Kinase Receptors in Astroglia Mol. Endocrinol., November 1, 2003; 17(11): 2365 - 2376. [Abstract] [Full Text] [PDF]

				J. Hou, B. Li, Z. Yang, N. Fager, and M. Y. J. Ma Altered Gene Activity of Epidermal Growth Factor Receptor (ErbB-1) in the Hypothalamus of Aging Female Rat Is Linked to Abnormal Estrous Cycles Endocrinology, February 1, 2002; 143(2): 577 - 586. [Abstract] [Full Text] [PDF]

				E. M. Apostolakis, J. Garai, J. E. Lohmann, J. H. Clark, and B. W. O’Malley Epidermal Growth Factor Activates Reproductive Behavior Independent of Ovarian Steroids in Female Rodents Mol. Endocrinol., July 1, 2000; 14(7): 1086 - 1098. [Abstract] [Full Text]

				S. R. Ojeda, J. Hill, D. F. Hill, M. E. Costa, V. Tapia, A. Cornea, and Y. J. Ma The Oct-2 POU Domain Gene in the Neuroendocrine Brain: A Transcriptional Regulator of Mammalian Puberty Endocrinology, August 1, 1999; 140(8): 3774 - 3789. [Abstract] [Full Text]

				A. G. Rabchevsky, J. M. Weinitz, M. Coulpier, C. Fages, M. Tinel, and M.-P. Junier A Role for Transforming Growth Factor alpha  as an Inducer of Astrogliosis J. Neurosci., December 15, 1998; 18(24): 10541 - 10552. [Abstract] [Full Text] [PDF]

				F. Rage, D. F. Hill, M. Sena-Esteves, X. O. Breakefield, R. J. Coffey, M. E. Costa, S. M. McCann, and S. R. Ojeda Targeting transforming growth factor alpha  expression to discrete loci of the neuroendocrine brain induces female sexual precocity PNAS, March 18, 1997; 94(6): 2735 - 2740. [Abstract] [Full Text] [PDF]