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Molecular Endocrinology 15 (1): 172-183
Copyright © 2001 by The Endocrine Society

Normal Prenatal but Arrested Postnatal Sexual Development of Luteinizing Hormone Receptor Knockout (LuRKO) Mice

Fu-Ping Zhang, Matti Poutanen, Johannes Wilbertz and Ilpo Huhtaniemi

Department of Physiology (F.-P.Z., M.P., I.H.) Institute of Biomedicine University of Turku FIN-20520, Turku, Finland
Department of Cell and Molecular Biology (J.W.) Karolinska Institute S-17177 Stockholm, Sweden

To study further the role of gonadotropins in reproductive functions, we generated mice with LH receptor (LHR) knockout (LuRKO) by inactivating, through homologous recombination, exon 11 on the LHR gene. LuRKO males and females were born phenotypically normal, with testes, ovaries, and genital structures indistinguishable from their wild-type (WT) littermates. Postnatally, testicular growth and descent, and external genital and accessory sex organ maturation, were blocked in LuRKO males, and their spermatogenesis was arrested at the round spermatid stage. The number and size of Leydig cells were dramatically reduced. LuRKO females also displayed underdeveloped external genitalia and uteri postnatally, and their age of vaginal opening was delayed by 5–7 days. The (-/-) ovaries were smaller, and histological analysis revealed follicles up to the early antral stage, but no preovulatory follicles or corpora lutea. Reduced gonadal sex hormone production was found in each sex, as was also reflected by the suppressed accessory sex organ weights and elevated gonadotropin levels. Completion of meiosis of testicular germ cells in the LuRKO males differs from other hypogonadotropic/cryptorchid mouse models, suggesting a role for FSH in this process. In females, FSH appears to stimulate developing follicles from the preantral to early antral stage, and LH is the stimulus beyond this stage. Hence, in each sex, the intrauterine sex differentiation is independent of LH action, but it has a crucial role postnatally for attaining sexual maturity. The LuRKO mouse is a close phenocopy of recently characterized human patients with inactivating LHR mutations, although the lack of pseudohermaphroditism in LuRKO males suggests that the intrauterine sex differentiation in this species is not dependent on LH action.




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Endocrinology, August 1, 2003; 144(8): 3329 - 3337.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. J. Yarram, M. J. Perry, T. J. Christopher, K. Westby, N. L. Brown, T. Lamminen, S. B. Rulli, F.-P. Zhang, I. Huhtaniemi, J. R. Sandy, et al.
Luteinizing Hormone Receptor Knockout (LuRKO) Mice and Transgenic Human Chorionic Gonadotropin (hCG)-Overexpressing Mice (hCG {alpha}{beta}+) Have Bone Phenotypes
Endocrinology, August 1, 2003; 144(8): 3555 - 3564.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. J. Guigon, S. Mazaud, M. G. Forest, S. Brailly-Tabard, N. Coudouel, and S. Magre
Unaltered Development of the Initial Follicular Waves and Normal Pubertal Onset in Female Rats after Neonatal Deletion of the Follicular Reserve
Endocrinology, August 1, 2003; 144(8): 3651 - 3662.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
J. Gromoll, J. Wistuba, N. Terwort, M. Godmann, T. Muller, and M. Simoni
A New Subclass of the Luteinizing Hormone/Chorionic Gonadotropin Receptor Lacking Exon 10 Messenger RNA in the New World Monkey (Platyrrhini) Lineage
Biol Reprod, July 1, 2003; 69(1): 75 - 80.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
M. M. Matzuk, F. J. DeMayo, L. A. Hadsell, and T. R. Kumar
Overexpression of Human Chorionic Gonadotropin Causes Multiple Reproductive Defects in Transgenic Mice
Biol Reprod, July 1, 2003; 69(1): 338 - 346.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. F. Couse, M. M. Yates, V. R. Walker, and K. S. Korach
Characterization of the Hypothalamic-Pituitary-Gonadal Axis in Estrogen Receptor (ER) Null Mice Reveals Hypergonadism and Endocrine Sex Reversal in Females Lacking ER{alpha} But Not ER{beta}
Mol. Endocrinol., June 1, 2003; 17(6): 1039 - 1053.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
N. J. Barlow, S. L. Phillips, D. G. Wallace, M. Sar, K. W. Gaido, and P. M. D. Foster
Quantitative Changes in Gene Expression in Fetal Rat Testes following Exposure to Di(n-butyl) Phthalate
Toxicol. Sci., June 1, 2003; 73(2): 431 - 441.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
T. Muller, J. Gromoll, and M. Simoni
Absence of Exon 10 of the Human Luteinizing Hormone (LH) Receptor Impairs LH, But Not Human Chorionic Gonadotropin Action
J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2242 - 2249.
[Abstract] [Full Text] [PDF]

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 Mol Hum ReprodHome page
R. Ivell and S. Hartung
The molecular basis of cryptorchidism
Mol. Hum. Reprod., April 1, 2003; 9(4): 175 - 181.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
Z.M. Lei, W. Zou, S. Mishra, X. Li, and Ch. V. Rao
Epididymal Phenotype in Luteinizing Hormone Receptor Knockout Animals and Its Response to Testosterone Replacement Therapy
Biol Reprod, March 1, 2003; 68(3): 888 - 895.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. Haywood, J. Spaliviero, M. Jimemez, N. J. C. King, D. J. Handelsman, and C. M. Allan
Sertoli and Germ Cell Development in Hypogonadal (hpg) Mice Expressing Transgenic Follicle-Stimulating Hormone Alone or in Combination with Testosterone
Endocrinology, February 1, 2003; 144(2): 509 - 517.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. J. Baker, P. Pakarinen, I. T. Huhtaniemi, M. H. Abel, H. M. Charlton, T. R. Kumar, and P. J. O'Shaughnessy
Failure of Normal Leydig Cell Development in Follicle-Stimulating Hormone (FSH) Receptor-Deficient Mice, But Not FSH{beta}-Deficient Mice: Role for Constitutive FSH Receptor Activity
Endocrinology, January 1, 2003; 144(1): 138 - 145.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
R. A. Anderson and D. T. Baird
Male Contraception
Endocr. Rev., December 1, 2002; 23(6): 735 - 762.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
M. Conti
Specificity of the Cyclic Adenosine 3',5'-Monophosphate Signal in Granulosa Cell Function
Biol Reprod, December 1, 2002; 67(6): 1653 - 1661.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. Pakarinen, S. Kimura, F. El-Gehani, L. J. Pelliniemi, and I. Huhtaniemi
Pituitary Hormones Are Not Required for Sexual Differentiation of Male Mice: Phenotype of the T/ebp/Nkx2.1 Null Mutant Mice
Endocrinology, November 1, 2002; 143(11): 4477 - 4482.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. Haywood, N. Tymchenko, J. Spaliviero, A. Koch, M. Jimenez, J. Gromoll, M. Simoni, V. Nordhoff, D. J. Handelsman, and C. M. Allan
An Activated Human Follicle-Stimulating Hormone (FSH) Receptor Stimulates FSH-Like Activity in Gonadotropin-Deficient Transgenic Mice
Mol. Endocrinol., November 1, 2002; 16(11): 2582 - 2591.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. B. Rulli, A. Kuorelahti, O. Karaer, L. J. Pelliniemi, M. Poutanen, and I. Huhtaniemi
Reproductive Disturbances, Pituitary Lactotrope Adenomas, and Mammary Gland Tumors in Transgenic Female Mice Producing High Levels of Human Chorionic Gonadotropin
Endocrinology, October 1, 2002; 143(10): 4084 - 4095.
[Abstract] [Full Text] [PDF]

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K. H. Burns and M. M. Matzuk
Minireview: Genetic Models for the Study of Gonadotropin Actions
Endocrinology, August 1, 2002; 143(8): 2823 - 2835.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
G. E. Owens, R. A. Keri, and J. H. Nilson
Ovulatory Surges of Human CG Prevent Hormone-Induced Granulosa Cell Tumor Formation Leading to the Identification of Tumor-Associated Changes in the Transcriptome
Mol. Endocrinol., June 1, 2002; 16(6): 1230 - 1242.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
M. Ascoli, F. Fanelli, and D. L. Segaloff
The Lutropin/Choriogonadotropin Receptor, A 2002 Perspective
Endocr. Rev., April 1, 2002; 23(2): 141 - 174.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. Romero, A. Paredes, G. A. Dissen, and S. R. Ojeda
Nerve Growth Factor Induces the Expression of Functional FSH Receptors in Newly Formed Follicles of the Rat Ovary
Endocrinology, April 1, 2002; 143(4): 1485 - 1494.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
T. Hirakawa, C. Galet, and M. Ascoli
MA-10 Cells Transfected with the Human Lutropin/Choriogonadotropin Receptor (hLHR): A Novel Experimental Paradigm to Study the Functional Properties of the hLHR
Endocrinology, March 1, 2002; 143(3): 1026 - 1035.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
P. R. Manna, L. Joshi, V. N. Reinhold, M. L. Aubert, N. Suganuma, K. Pettersson, and I. T. Huhtaniemi
Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone
Hum. Mol. Genet., February 1, 2002; 11(3): 301 - 315.
[Abstract] [Full Text] [PDF]

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 J. Cell Sci.Home page
P. J. O'Shaughnessy, H. Johnston, L. Willerton, and P. J. Baker
Failure of normal adult Leydig cell development in androgen-receptor-deficient mice
J. Cell Sci., January 9, 2002; 115(17): 3491 - 3496.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
I. A. Hughes
Minireview: Sex Differentiation
Endocrinology, August 1, 2001; 142(8): 3281 - 3287.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
F. El-Gehani, M. Tena-Sempere, H. Ruskoaho, and I. Huhtaniemi
Natriuretic Peptides Stimulate Steroidogenesis in the Fetal Rat Testis
Biol Reprod, August 1, 2001; 65(2): 595 - 600.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. B. Seminara and W. F. Crowley Jr.
Perspective: The Importance of Genetic Defects in Humans in Elucidating the Complexities of the Hypothalamic-Pituitary-Gonadal Axis
Endocrinology, June 1, 2001; 142(6): 2173 - 2177.
[Full Text] [PDF]

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J. S. Richards
Perspective: The Ovarian Follicle--A Perspective in 2001
Endocrinology, June 1, 2001; 142(6): 2184 - 2193.
[Full Text] [PDF]


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