Abstract
Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births1. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase1,2,3. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily4 expressed in the developing testis5. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hutson, J.M., Baker, M., Terada, M., Zhou, B. & Paxton, G. Hormonal control of testicular descent and the cause of cryptorchidism. Reprod. Fertil. Dev. 6, 151–156 (1994).
Hutson, J.M. A biphasic model for the hormonal control of testicular descent. Lancet 2, 419–421 ( 1985).
Satokata, I., Benson, G. & Maas, R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice. Nature 374, 460–463 (1995).
Adham, I.M., Burkhardt, E., Benahmed, M. & Engel, W. Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J. Biol. Chem. 268, 26668– 26672 (1993).
Zimmermann, S., Schottler, P., Engel, W. & Adham, I.M. Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol. Reprod. Dev. 47, 30– 38 (1997).
Zhu, Y., Richardson, J.A., Parada, L.F. & Graff, J.M. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703–714 (1998).
Nishimune, Y., Aizawa, S. & Komatsu, T. Testicular germ cell differentiation in vivo. Fertil. Steril. 29, 95–102 (1978).
Griffiths, A.L., Momose, Y. & Hutson, J.M. The gubernaculum in adult female, adult male and TFM male mice. Int. J. Androl. 16, 380– 384 (1993).
Lyon, M.F. & Hawkes, S.G. X-linked gene for testicular feminization in the mouse. Nature 227, 1217– 1219 (1970).
Radovick, S. et al. Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice. Proc. Natl Acad. Sci. USA 88, 3402–3406 (1991).
Thomson, A.A., Foster, B.A. & Cunha, G.R. Analysis of growth factor and receptor mRNA levels during development of the rat seminal vesicle and prostate. Development 124, 2431–2439 ( 1997).
Wilson, J.D., Griffin, J.E., George, F.W. & Leshin, M. The role of gonadal steroids in sexual differentiation. Recent Prog. Horm. Res. 37, 1–39 (1981).
Wilson, J.D., Griffin, J.E., George, F.W. & Leshin, M. The endocrine control of male phenotypic development. Aust. J. Biol. Sci. 36, 101–128 ( 1983).
Tsuji, M. et al. Later onset of apoptosis in the bulbourethral glands after castration compared to that in the seminal vesicles. J. Steroid Biochem. Mol. Biol. 67, 113–118 (1998).
Wensing, C.J. The embryology of testicular descent. Horm. Res. 30 , 144–152 (1988).
Fentener, v.V.J.M., van Zoelen, E.J., Ursem, P.J. & Wensing, C.J. In vitro model of the first phase of testicular descent: identification of a low molecular weight factor from fetal testis involved in proliferation of gubernaculum testis cells and distinct from specified polypeptide growth factors and fetal gonadal hormones. Endocrinology 123, 2868–2877 (1988).
Visser, J.H. & Heyns, C.F. Proliferation of gubernaculum cells induced by a substance of low molecular mass obtained from fetal pig testes. J. Urol. 153, 516–520 (1995).
Husmann, D.A. & Levy, J.B. Current concepts in the pathophysiology of testicular undescent. Urology 46, 267 –276 (1995).
Berkowitz, G.S. et al. Prevalence and natural history of cryptorchidism. Pediatrics 92, 44–49 ( 1993).
Zarrow, M.X. Experimental Endocrinology, A Source Book of Basic Technics (Academic Press, New York, 1964).
Zimmermann, S. et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol. Endocrinol. 13, 681 –691 (1999).
Shono, T. et al. Scanning electron microscopy shows inhibited gubernacular development in relation to undescended testes in oestrogen-treated mice. Int. J. Androl. 19, 263–270 ( 1996).
Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 ( 1993).
Liebl, D.J., Tessarollo, L., Palko, M.E. & Parada, L.F. Absence of sensory neurons before target innervation in brain-derived neurotrophic factor-, neurotrophin 3-, and TrkC-deficient embryonic mice. J. Neurosci. 17, 9113–9121 (1997).
Nef, S. & Nef, P. Olfaction: transient expression of a putative odorant receptor in the avian notochord. Proc. Natl Acad. Sci. USA 94, 4766–4771 ( 1997).
Resko, J.A., Malley, A., Begley, D. & Hess, D.L. Radioimmunoassay of testosterone during fetal development of the rhesus monkey. Endocrinology 93, 156–161 (1973).
Acknowledgements
We thank J. Wilson, J. Graff, W. Neaves and D. Russel for discussion and comments on the manuscript; T. Shipman and S. Karzhai for technical support; G. Lawton for assistance with SEM pictures; and D. Hess for testosterone measurements. This work was supported in part by a grant from the Swiss National Science Foundation (S.N., 81GE-18118) and by Excellence in Education Grant (L.F.P. and S.N.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nef, S., Parada, L. Cryptorchidism in mice mutant for Insl3. Nat Genet 22, 295–299 (1999). https://doi.org/10.1038/10364
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/10364
This article is cited by
-
The curious case of testicular descent: factors controlling testicular descent with a note on cryptorchidism
African Journal of Urology (2023)
-
Tmsb10 triggers fetal Leydig differentiation by suppressing the RAS/ERK pathway
Communications Biology (2022)
-
Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2
Communications Biology (2022)
-
Insulin-like 3 affects zebrafish spermatogenic cells directly and via Sertoli cells
Communications Biology (2021)
-
Evidence for existence of insulin-like factor 3 (INSL3) hormone-receptor system in the ovarian corpus luteum and extra-ovarian reproductive organs during pregnancy in goats
Cell and Tissue Research (2021)