This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gyurko, R. Articles by Huang, P. L. Search for Related Content PubMed PubMed Citation Articles by Gyurko, R. Articles by Huang, P. L.

Deletion of Exon 6 of the Neuronal Nitric Oxide Synthase Gene in Mice Results in Hypogonadism and Infertility

Cardiovascular Research Center and Reproductive Endocrine Unit (S.L.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129

Address all correspondence and requests for reprints to: Paul L. Huang, M.D., Ph.D., Cardiovascular Research Center, Massachusetts General Hospital, 149 Thirteenth Street, Charlestown, Massachusetts 02129-2060. E-mail: . huangp{at}helix.mgh.harvard.edu

Nitric oxide (NO) has been recognized as a modulator in reproductive functions, but it is not clear whether NO is required for fertility. The first line of mice deficient in neuronal NO synthase (referred to herein as KN1 mice) reproduce normally. However, residual neuronal NO synthase (nNOS) activity is detected in KN1 mice due to the expression of ß- and -nNOS splice variants. We generated a new line of nNOS knockout mice (KN2) lacking exon 6, which codes for the heme-binding domain of nNOS. KN2 mice are viable, but mated homozygotes do not produce litters, indicating that either one or both sexes are infertile. Male KN2 mice show decreased gonad weights, but sperm counts are normal. KN2 males do not display mating behavior, and consequently do not leave vaginal plugs when housed with wild-type (WT) females. KN2 females show decreased ovary weight, and histology reveals decreased corpus luteum counts. RIAs show that KN2 males have decreased plasma FSH, whereas KN2 females have increased levels of plasma LH and increased hypothalamic GnRH content. Experimental ovarian transplantation suggests that central, rather than ovarian, processes are influenced by nNOS, as KN2 ovaries ovulate at near-normal rates under WT hormonal control, whereas WT ovaries transplanted into KN2 mice have decreased ovulation rates. We observed pyloric stenosis in KN2 mice, but plasma leptin levels are normal, and no ketones are found, indicating that hypogonadism is not a result of malnutrition. We conclude that nNOS is required for normal central hormonal regulation of reproductive function.

This article has been cited by other articles:

				M. A. Edson, A. K. Nagaraja, and M. M. Matzuk The Mammalian Ovary from Genesis to Revelation Endocr. Rev., October 1, 2009; 30(6): 624 - 712. [Abstract] [Full Text] [PDF]

				B. A. Weissman, C. M. Sottas, M. Holmes, P. Zhou, C. Iadecola, D. O. Hardy, R.-S. Ge, and M. P. Hardy Normal Responses to Restraint Stress in Mice Lacking the Gene for Neuronal Nitric Oxide Synthase J Androl, September 1, 2009; 30(5): 614 - 620. [Abstract] [Full Text] [PDF]

				Y. M. Rao, A. Chaudhury, and R. K. Goyal Active and inactive pools of nNOS in the nerve terminals in mouse gut: implications for nitrergic neurotransmission Am J Physiol Gastrointest Liver Physiol, March 1, 2008; 294(3): G627 - G634. [Abstract] [Full Text] [PDF]

				J. Clasadonte, P. Poulain, J.-C. Beauvillain, and V. Prevot Activation of Neuronal Nitric Oxide Release Inhibits Spontaneous Firing in Adult Gonadotropin-Releasing Hormone Neurons: A Possible Local Synchronizing Signal Endocrinology, February 1, 2008; 149(2): 587 - 596. [Abstract] [Full Text] [PDF]

				V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]

				X. d'Anglemont de Tassigny, C. Campagne, B. Dehouck, D. Leroy, G. R. Holstein, J.-C. Beauvillain, V. Buee-Scherrer, and V. Prevot Coupling of Neuronal Nitric Oxide Synthase to NMDA Receptors via Postsynaptic Density-95 Depends on Estrogen and Contributes to the Central Control of Adult Female Reproduction J. Neurosci., June 6, 2007; 27(23): 6103 - 6114. [Abstract] [Full Text] [PDF]

				A. Friebe, E. Mergia, O. Dangel, A. Lange, and D. Koesling Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase PNAS, May 1, 2007; 104(18): 7699 - 7704. [Abstract] [Full Text] [PDF]

				J. Lapointe, M. Roy, I. St-Pierre, S. Kimmins, D. Gauvreau, L. A. MacLaren, and J.-F. Bilodeau Hormonal and Spatial Regulation of Nitric Oxide Synthases (NOS) (Neuronal NOS, Inducible NOS, and Endothelial NOS) in the Oviducts Endocrinology, December 1, 2006; 147(12): 5600 - 5610. [Abstract] [Full Text] [PDF]

				K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]

				K. J. Hurt, S. F. Sezen, H. C. Champion, J. K. Crone, M. A. Palese, P. L. Huang, A. Sawa, X. Luo, B. Musicki, S. H. Snyder, et al. Alternatively spliced neuronal nitric oxide synthase mediates penile erection PNAS, February 28, 2006; 103(9): 3440 - 3443. [Abstract] [Full Text] [PDF]

				T. Morishita, M. Tsutsui, H. Shimokawa, K. Sabanai, H. Tasaki, O. Suda, S. Nakata, A. Tanimoto, K.-Y. Wang, Y. Ueta, et al. Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms PNAS, July 26, 2005; 102(30): 10616 - 10621. [Abstract] [Full Text] [PDF]

				E. Cakir, O. Ozcan, H. Yaman, E. O. Akgul, C. Bilgi, M. K. Erbil, and Z. Yesilova Elevated Plasma Concentration of Asymmetric Dimethylarginine That Is Reduced by Single Dose Testosterone Administration in Idiopathic Hypogonadotropic Hypogonadism Patients J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1651 - 1654. [Abstract] [Full Text] [PDF]

				H.-F. Huang, B. Wang, X.-F. Yang, Q. Luo, and J.-Z. Sheng Nitric Oxide Mediates Inhibitory Effect of Leptin on Insulin-Like Growth Factor I Augmentation of 17{beta}-Estradiol Production in Human Granulosa Cells Biol Reprod, January 1, 2005; 72(1): 102 - 106. [Abstract] [Full Text] [PDF]

				R. J. van't Hof, J. MacPhee, H. Libouban, M. H. Helfrich, and S. H. Ralston Regulation of Bone Mass and Bone Turnover by Neuronal Nitric Oxide Synthase Endocrinology, November 1, 2004; 145(11): 5068 - 5074. [Abstract] [Full Text] [PDF]

				R. von Coelln, B. Thomas, J. M. Savitt, K. L. Lim, M. Sasaki, E. J. Hess, V. L. Dawson, and T. M. Dawson Loss of locus coeruleus neurons and reduced startle in parkin null mice PNAS, July 20, 2004; 101(29): 10744 - 10749. [Abstract] [Full Text] [PDF]

				R. Gros, T. Afroze, X.-M. You, G. Kabir, R. Van Wert, W. Kalair, A. E. Hoque, I. N. Mungrue, and M. Husain Plasma Membrane Calcium ATPase Overexpression in Arterial Smooth Muscle Increases Vasomotor Responsiveness and Blood Pressure Circ. Res., October 3, 2003; 93(7): 614 - 621. [Abstract] [Full Text] [PDF]

				L. K. Bachir, G. Garrel, A. Lozach, J.-N. Laverriere, and R. Counis The Rat Pituitary Promoter of the Neuronal Nitric Oxide Synthase Gene Contains an Sp1-, LIM Homeodomain-Dependent Enhancer and a Distinct Bipartite Gonadotropin-Releasing Hormone-Responsive Region Endocrinology, September 1, 2003; 144(9): 3995 - 4007. [Abstract] [Full Text] [PDF]