Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Modelling genitourinary defects in mice: an emerging genetic and developmental system

Nature Reviews Genetics volume 4, pages 478–482 (2003)Cite this article

Abstract

The rising incidence of genitourinary (GU) defects among newborns establishes the need and opportunity to focus research efforts on the amelioration of this growing public-health concern. Sadly, our inability to explain the causes of GU defects can be directly attributed to our lack of understanding of GU gene function. Recently, mouse models have been used to provide new insights into the mechanisms that underlie congenital GU malformations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stages of human genitourinary development.
Figure 2: Anatomical classes of hypospadia.
Figure 3: Analysis of common developmental themes in the genitourinary region of E12.5 male mouse embryos.
Figure 4: Establishment of the urethral epithelium as a signalling centre.
Figure 5: Loss of Hoxa13 function affects the maturation and stratification of the urethral epithelium.

Similar content being viewed by others

References

  1. Giwercman, A., Carlsen, E., Keiding, N. & Skakkenbaek, N. E. Evidence for increasing incidence of abnormalities of the human testis: a review. Environ. Health Perspect. 2, 65–71 (1993).

    Google Scholar 

  2. Paulozzi, L. J., Erickson, D. & Jackson, R. J. Hypospadias trends in two US surveillance systems. Pediatrics 100, 831–834 (1997).

    Article  CAS  Google Scholar 

  3. Gallentine, M. L., Morey, A. F. & Thompson, I. M. Hypospadias: a contemporary epidemiologic assessment. Urology 57, 788–790 (2001).

    Article  CAS  Google Scholar 

  4. Sadler, T. W. Langman's Medical Embryology 7th edn 299–310 (Lippincott, Williams and Wilkins, New York, 1995).

    Google Scholar 

  5. Arey, L. B. Developmental Anatomy 6th edn 330–339 (Saunders Company, Philadelphia, 1954).

    Google Scholar 

  6. Murakami, R. A histological study of the development of the penis of wild-type and androgen-insensitive mice. J. Anat. 153, 223–231 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolf, C. et al. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodine, chlozolinate, p,p′-DDE, and ketaconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicol. Ind. Health 15, 94–118 (1999).

    Article  Google Scholar 

  8. Ostby, J., Monosson, E., Kelce, W. R. & Gray, L. E. Envrionmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation in the male rat. Toxicol. Ind. Health 15, 48–64 (1999).

    Article  Google Scholar 

  9. Schardein, J. L. Chemically Induced Birth Defects 271–339 (Dekker, New York, 1993).

    Google Scholar 

  10. Clark, R. L. et al. External genitalia abnormalities in male rats exposed to finasteride, a 5-α reductase inhibitor. Teratology 42, 91–100 (1990).

    Article  CAS  Google Scholar 

  11. Prahalada, S. et al. Effects of finasteride, a type-2 5-α reductase inhibitor on fetal development of the rhesus monkey (Macaca mulatta). Teratology 55, 119–131 (1997).

    Article  CAS  Google Scholar 

  12. Kelce, W. R. & Wilson, E. M. Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications. J. Mol. Med. 75, 198–207 (1997).

    Article  CAS  Google Scholar 

  13. Kaloo, N. B., Gearhart, J. P. & Barrack, J. R. Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia. J. Clin. Endocrinol. Metab. 77, 692–698 (1993).

    Google Scholar 

  14. Labrie, C. et al. Combination of an antiandrogen and a 5 α-reductase inhibitor: a further step towards total androgen blockade? Endocrinology 129, 566–568 (1991).

    CAS  PubMed  Google Scholar 

  15. Svensson, H., Reychman, M., Troeng, T. & Aberg, M. Staged reconstruction of hypospadias with chordee: outcome and costs. Scan. J. Plast. Reconst. Surg. Hand Surg. 31, 51–55 (1997).

    Article  CAS  Google Scholar 

  16. Perriton, C. L., Powles, N., Chiang, C., Maconochie, M. K. & Cohn, M. J. Sonic hedgehog signalling from the urethral plate epithelium controls external genitalia development. Dev. Biol. 247, 26–46 (2002).

    Article  CAS  Google Scholar 

  17. Capecchi, M. R. Choose your target. Nature Genet. 26, 159–161 (2000).

    Article  CAS  Google Scholar 

  18. Anagnostopoulos, A. V., Mobraaten, L. E., Sharp, J. J. & Davisson, M. T. Transgenic and knockout databases: behavioral profiles of mouse mutants. Physiol. Behav. 73, 675–689 (2001).

    Article  CAS  Google Scholar 

  19. Baskin, L. S. Hypospadias and urethral development. J. Urol. 163, 951–956 (2000).

    Article  CAS  Google Scholar 

  20. Minelli, A. Homology, limbs and genitalia. Evol. Dev. 4, 127–132 (2002).

    Article  Google Scholar 

  21. Suzuki, K. et al. Embryonic development of the mouse genitalia: insights into a unique mode of organogenesis. Evol. Dev. 4, 133–141 (2002).

    Article  Google Scholar 

  22. Haraguchi, R. et al. Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development 127, 2471–2479 (2000).

    CAS  PubMed  Google Scholar 

  23. Haraguchi, R. et al. Unique functions of Sonic hedgehog during external genitalia development. Development 128, 4241–4250 (2001).

    CAS  PubMed  Google Scholar 

  24. Morgan, E. A., Nguyen, S. B., Scott, V. L. & Stadler, H. S. Loss of Fgf-8 and Bmp-7 signaling in Hoxa13 mutant mice cause hypospadia. Development (in the press).

  25. de Santa Barbara, P. & Roberts, D. J. Tail gut endoderm and gut/genitourinary/tail development: new tissue-specific role for Hoxa13. Development 129, 551–561 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Stern, A. M. et al. The hand–foot–uterus syndrome: a new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic, abnormalities, and partial duplication of the female genital tract. J. Pediatr. 77, 109–116 (1970).

    Article  CAS  Google Scholar 

  27. Mortlock, D. P. & Innis, J. W. Mutation of HOXA13 in hand–foot–genital syndrome. Nature Genet. 156, 179–180 (1997).

    Article  Google Scholar 

  28. Fromental-Ramain, C. et al. Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development 122, 2997–3011 (1997).

    Google Scholar 

  29. Post, L. C. & Innis, J. W. Infertility in adult hypodactyly mice is associated with hypospadia of distal reproductive structures. Biol. Reprod. 61, 1402–1408 (1999).

    Article  CAS  Google Scholar 

  30. Warot, X., Fromental-Ramain, C., Fraulob, V., Chambon, P. & Dollé, P. Gene dosage-dependent effects of Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive system and urogenital tracts. Development 124, 4781–4791 (1997).

    CAS  PubMed  Google Scholar 

  31. Stadler, H. S., Higgins, K. M. & Capecchi, M. R. Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Development 128, 4177–4188 (2001).

    CAS  PubMed  Google Scholar 

  32. Hartman, C. & Tabin, C. J. Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127, 3141–3159 (2000).

    Google Scholar 

  33. Hamblet, N. S. et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation, and neural tube closure. Development 129, 5827–5838 (2002).

    Article  CAS  Google Scholar 

  34. Holmberg, J., Clarke, D. L. & Frisen, J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408, 203–206 (2000).

    Article  CAS  Google Scholar 

  35. Podlasek, C. A., Duboule, D. & Bushman, W. Male accessory sex organ morphogenesis is altered by loss of function of Hoxd13. Dev. Dyn. 208, 454–465 (1997).

    Article  CAS  Google Scholar 

  36. Oefelein, M., Chin-Chance, C. & Bushman, W. Expression of the homeotic gene Hoxd13 in the developing and adult mouse prostate. J. Urol. 155, 342–346 (1996).

    Article  CAS  Google Scholar 

  37. Zelster, L., Desplan, C. & Heintz, N. Hoxb-13: a new Hox gene in a distant region of the Hox B cluster maintains colinearity. Development 122, 2475–2484 (1996).

    Google Scholar 

  38. Steers, W. D. 5 α-reductase activity in the prostate. Urology 58, 17–24 (2001).

    Article  CAS  Google Scholar 

  39. Sreenath, T., Orosz, A., Fujita, K. & Bieberich, C. J. Androgen-independent expression of Hoxb13 in the mouse prostate. Prostate 41, 203–207 (1999).

    Article  CAS  Google Scholar 

  40. Podlasek, C. A. et al. Hoxa10 deficient mice exhibit abnormal development of the accessory sex organs. Dev. Dyn. 214, 1–12 (1999).

    Article  CAS  Google Scholar 

  41. Baskin, L. S. et al. Urethral seam formation and hypospadias. Cell Tissue Res. 305, 379–387 (2001).

    Article  CAS  Google Scholar 

  42. Anderson, C. A. & Clark, R. L. External genitalia of the rat: normal development and the histogenesis of 5 α-reductase inhibitor-induced abnormalities. Teratology 42, 483–496 (1990).

    Article  CAS  Google Scholar 

  43. Miller, C., Degenhardt, K. & Sassoon, D. A. Fetal exposure to DES results in de-regulation of Wnt-7a during uterine morphogenesis. Nature Genet. 20, 228–230 (1998).

    Article  CAS  Google Scholar 

  44. Liang, M., Benson, G. V., Lim, H., Dey, S. K. & Maas, R. L. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in Mullerian duct by synthetic estrogen diethylstilbestrol (DES). Dev. Biol. 197, 141–154 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

The author thanks D. Stadler for the critical reading of this manuscript and S. Nguyen, E. Morgan and V. Scott for expert technical assistance. A portion of this work was supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disorders, and the March of Dimes Birth Defects Foundation (Basil O'Connor Starter Scholar Research Award Grant).

Author information

Authors and Affiliations

  1. Shriners Hospital for Children and the Oregon Health and Science University, 3101 SW Sam Jackson Park Road, Portland, 97239, Oregon, USA

    H. Scott Stadler

Authors
  1. H. Scott Stadler
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Entrez

Bmp4

Bmp7

Fgf8

Fgf10

Hoxa10

Hoxa13

Hoxd13

Shh

LocusLink

Bmp7

Fgf8

Hoxa10

Hoxa13

HOXA13

Hoxb13

Shh

Wnt7a

OMIM

hand–foot–genital syndrome

Glossary

CORONAL HYPOSPADIA

A malformation of the distal portion of the penis in which the urinary opening is misplaced.

FINASTERIDE

An inhibitor of the enzyme 5-β reductase that converts testosterone to dihydroxytestosterone (a potent androgen used during the masculinization of the male fetus).

FOCAL SCULPTING

A developmental process that removes cells or tissues by programmed cell death, which facilitates the formation or differentiation of an embryonic region.

HYPOPLASIA

The underdevelopment of a tissue or organ.

HYPOSPADIA

A developmental defect that affects the growth and closure of the ventral urethra, meatus or scrotum.

OS-CLITORIS

A structure found in female mice, which differs from the human clitoris by the presence of an ossified region of endochondral and membranous bone. Homologous to the os-penis in male mice.

OS-PENIS

A structure found in male mice, which differs from the human penis by the presence of an ossified region of endochondral and membranous bone. Homologous to the os-clitoris in female mice.

PARALOGUES

Genes that are related by duplication in a genome, which have evolved new functions

PERITONEAL HYPOSPADIA

A malformation of the base of the external genitalia and body wall, which remains open in affected individuals.

STRATIFICATION

The layered differentiated state of epithelial cells that line many of the genitourinary structures.

TERATOGEN

An agent that causes the malformation of a developing fetus; for example, chemicals, viruses and ionizing radiation.

TUNEL ASSAY

(Terminal dUTP nick-end-labelling assay). An enzymatic process that labels the 3′ ends of DNA in a cell that is undergoing programmed cell death.

URETHRAL EPITHELIUM

(UE). A centrally located layer of cells in the developing genital tubercle that secretes many of the growth factors that are required for normal genitourinary development.

URETHRAL HYPOSPADIA

A defect in closure of the primary shaft of the penis in which multiple openings form.

VINCLOZOLIN

A protectant nonsystemic dicarboximide fungicide that exhibits antiandrogenic activity in mammals. It is used mainly on oilseed rape and peas in the United Kingdom, and on vines, fruit and vegetables in the United States.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stadler, H. Modelling genitourinary defects in mice: an emerging genetic and developmental system. Nat Rev Genet 4, 478–482 (2003). https://doi.org/10.1038/nrg1083

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1083

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing