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.

  • Review Article
  • Published:

Developmental genetics of the female reproductive tract in mammals

Nature Reviews Genetics volume 4, pages 969–980 (2003)Cite this article

Key Points

  • The female reproductive tract, which includes the oviducts, uterus, cervix and vagina, is derived from the Müllerian ducts that form in both male and female fetuses.

  • The Müllerian ducts are composed of a simple epithelium and surrounding mesenchyme, which give rise to the endometrium and myometrium, respectively, of the uterus.

  • The extent and position of Müllerian duct fusion results in the diverse morphology of the mammalian female reproductive tracts.

  • Elimination of the Müllerian ducts in male fetuses is caused by Müllerian inhibiting substance, which is a hormone that is secreted by the fetal testes.

  • A small number of transcription factors that are expressed in the Müllerian duct epithelium are required for its formation and maintenance.

  • Wnt signalling regulates Müllerian duct formation, differentiation and regression.

  • Hox genes specify the anterior-posterior patterning of the Müllerian duct system.

  • The synthetic oestrogen diethylstilbestrol disturbs female reproductive tract development in both mice and humans.

  • Human congenital defects of the female reproductive tract include agenesis, atresia and septation.

  • Genetic pathways that regulate female reproductive tract development might be conserved between invertebrates and vertebrates.

Abstract

The female reproductive tract receives the oocytes for fertilization, supports the development of the fetus and provides the passage for birth. Although abnormalities of this organ system can result in infertility and even death, until recently relatively little was known about the genetic processes that underlie its development. By drawing primarily on mouse mutagenesis studies and the analysis of human mutations we review the emerging genetic pathways that regulate female reproductive-tract formation in mammals and that are implicated in congenital abnormalities of this organ system. We also show that these pathways might be conserved between invertebrates and mammals.

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: Female reproductive-tract variation in mammals.
Figure 2: Formation of the Müllerian ducts.
Figure 3: Müllerian duct regression.

Similar content being viewed by others

References

  1. Gidwani, G. & Falcone, T. Congenital Malformations of the Female Genital Tract: Diagnosis and Management (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  2. National, Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. [online], (cited 8 Oct. 2003), <http://www.seer.cancer.gov> (2003).

  3. Paria, B. C., Reese, J., Das, S. K. & Dey, S. K. Deciphering the cross-talk of implantation: advances and challenges. Science 296, 2185–2188 (2002).

    CAS  PubMed  Google Scholar 

  4. Couse, J. F. & Korach, K. S. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr. Rev. 20, 358–417 (1999).

    CAS  PubMed  Google Scholar 

  5. Feldhamer, G., Drickamer, L., Vessey, S. & Merritt, J. Mammalogy: Adaptation, Diversity, and Ecology (McGraw–Hill, New York, 2003).

    Google Scholar 

  6. Hill, J. E. & Smith, J. D. Bats: a Natural History (Univ. of Texas Press, Austin, 1984).

    Google Scholar 

  7. Chi, N. & Epstein, J. A. Getting your Pax straight: Pax proteins in development and disease. Trends Genet. 18, 41–47 (2002).

    CAS  PubMed  Google Scholar 

  8. Torres, M., Gomez-Pardo, E., Dressler, G. R. & Gruss, P. Pax-2 controls multiple steps of urogenital development. Development 121, 4057–4065 (1995).

    CAS  PubMed  Google Scholar 

  9. Mansouri, A., Chowdhury, K. & Gruss, P. Follicular cells of the thyroid gland require Pax8 gene function. Nature Genet. 19, 87–90 (1998).

    CAS  PubMed  Google Scholar 

  10. Bouchard, M., Souabni, A., Mandler, M., Neubuser, A. & Busslinger, M. Nephric lineage specification by Pax2 and Pax8. Genes Dev. 16, 2958–2970 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kobayashi, A., Shawlot, W., Kania, A. & Behringer, R. R. Requirement of Lim1 for female reproductive tract development. Development (in the press). This study describes the visualization of reproductive tract development in embryos and a new chimaera analysis for female organs is used to identify a cell-autonomous requirement of Lim1 in Müllerian duct formation.

  12. Miyamoto, N., Yoshida, M., Kuratani, S., Matsuo, I. & Aizawa, S. Defects of urogenital development in mice lacking Emx2. Development 124, 1653–1664 (1997).

    CAS  PubMed  Google Scholar 

  13. Mendelsohn, C. et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120, 2749–2771 (1994).

    CAS  PubMed  Google Scholar 

  14. Kastner, P. et al. Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124, 313–326 (1997).

    CAS  PubMed  Google Scholar 

  15. Miller, C., Pavlova, A. & Sassoon, D. A. Differential expression patterns of Wnt genes in the murine female reproductive tract during development and the estrous cycle. Mech. Dev. 76, 91–99 (1998).

    CAS  PubMed  Google Scholar 

  16. Jeays-Ward, K. et al. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 130, 3663–3670 (2003).

    CAS  PubMed  Google Scholar 

  17. Vainio, S., Heikkila, M., Kispert, A., Chin, N. & McMahon, A. P. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999). This study identifies the involvement of a Wnt pathway in Müllerian duct formation.

    CAS  PubMed  Google Scholar 

  18. Kuure, S., Vuolteenaho, R. & Vainio, S. Kidney morphogenesis: cellular and molecular regulation. Mech. Dev. 92, 31–45 (2000).

    CAS  PubMed  Google Scholar 

  19. Vainio, S. & Lin, Y. Coordinating early kidney development: lessons from gene targeting. Nature Rev. Genet 3, 533–543 (2002).

    CAS  PubMed  Google Scholar 

  20. Stark, K., Vainio, S., Vassileva, G. & McMahon, A. P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

    CAS  PubMed  Google Scholar 

  21. Rothenpieler, U. W. & Dressler, G. R. Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development 119, 711–720 (1993).

    CAS  PubMed  Google Scholar 

  22. Strong, L. C. & Hollander, W. F. Hereditary loop-tail in the house mouse accompanied by inperforate vagina and craniorachischisis when homozygous. J. Hered. 40, 329–334 (1949).

    Google Scholar 

  23. Kibar, Z. et al. Ltap, a mammalian homologue of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nature Genet. 28, 251–255 (2001).

    CAS  PubMed  Google Scholar 

  24. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    CAS  PubMed  Google Scholar 

  25. Heisenberg, C. P. & Tada, M. Wnt signalling: a moving picture emerges from van gogh. Curr. Biol. 12, 126–128 (2002).

    Google Scholar 

  26. Josso, N. et al. Anti-mullerian hormone: the Jost factor. Recent Prog. Horm. Res. 48, 1–59 (1993).

    CAS  PubMed  Google Scholar 

  27. Behringer, R. R., Finegold, M. J. & Cate, R. L. Mullerian-inhibiting substance function during mammalian sexual development. Cell 79, 415–425 (1994). This study provides evidence that MIS is essential for Müllerian duct regression.

    CAS  PubMed  Google Scholar 

  28. Behringer, R. R., Cate, R. L., Froelick, G. J., Palmiter, R. D. & Brinster, R. L. Abnormal sexual development in transgenic mice chronically expressing mullerian inhibiting substance. Nature 345, 167–170 (1990).

    CAS  PubMed  Google Scholar 

  29. Shen, W. H., Moore, C. C., Ikeda, Y., Parker, K. L. & Ingraham, H. A. Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: a link to the sex determination cascade. Cell 77, 651–661 (1994).

    PubMed  Google Scholar 

  30. De Santa Barbara, P. et al. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol. Cell Biol. 18, 6653–6665 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nachtigal, M. W. et al. Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93, 445–454 (1998).

    CAS  PubMed  Google Scholar 

  32. Arango, N. A., Lovell-Badge, R. & Behringer, R. R. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 99, 409–419 (1999).

    CAS  PubMed  Google Scholar 

  33. Roberts, L. M., Visser, J. A. & Ingraham, H. A. Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development. Development 129, 1487–1496 (2002).

    CAS  PubMed  Google Scholar 

  34. Dyche, W. J. A comparative study of the differentiation and involution of the Mullerian duct and Wolffian duct in the male and female fetal mouse. J. Morphol. 162, 175–209 (1979).

    CAS  PubMed  Google Scholar 

  35. Mishina, Y. et al. Genetic analysis of the Mullerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation. Genes Dev. 10, 2577–2587 (1996).

    CAS  PubMed  Google Scholar 

  36. Mishina, Y., Whitworth, D. J., Racine, C. & Behringer, R. R. High specificity of Mullerian-inhibiting substance signaling in vivo. Endocrinology 140, 2084–2088 (1999).

    CAS  PubMed  Google Scholar 

  37. Gouedard, L. et al. Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti-Mullerian hormone and its type II receptor. J. Biol. Chem. 275, 27973–27978 (2000).

    CAS  PubMed  Google Scholar 

  38. Clarke, T. R. et al. Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression. Mol. Endocrinol. 15, 946–959 (2001).

    CAS  PubMed  Google Scholar 

  39. Visser, J. A. et al. The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling. Mol. Endocrinol. 15, 936–945 (2001).

    CAS  PubMed  Google Scholar 

  40. Mishina, Y., Suzuki, A., Ueno, N. & Behringer, R. R. Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 9, 3027–3037 (1995).

    CAS  PubMed  Google Scholar 

  41. Jamin, S. P., Arango, N. A., Mishina, Y., Hanks, M. C. & Behringer, R. R. Requirement of Bmpr1a for Mullerian duct regression during male sexual development. Nature Genet. 32, 408–410 (2002).

    CAS  PubMed  Google Scholar 

  42. Parr, B. A. & McMahon, A. P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998). This study identifies the involvement of a Wnt pathway in Müllerian duct regression: Wnt7a expression in the Müllerian duct epithelium is required for the activation of MIS type II receptor expression in the Müllerian duct mesenchyme.

    CAS  PubMed  Google Scholar 

  43. Kawakami, Y., Wada, N., Nishimatsu, S. & Nohno, T. Involvement of frizzled-10 in Wnt-7a signaling during chick limb development. Dev. Growth Differ. 42, 561–569 (2000).

    CAS  PubMed  Google Scholar 

  44. Parr, B. A. & McMahon, A. P. Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature 374, 350–353 (1995).

    CAS  PubMed  Google Scholar 

  45. Allard, S. et al. Molecular mechanisms of hormone-mediated Mullerian duct regression: involvement of β-catenin. Development 127, 3349–3360 (2000).

    CAS  PubMed  Google Scholar 

  46. Itoh, T. et al. Unaltered secretion of β-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem. 272, 22389–22392 (1997).

    CAS  PubMed  Google Scholar 

  47. Kurita, T., Cooke, P. S. & Cunha, G. R. Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev. Biol. 240, 194–211 (2001).

    CAS  PubMed  Google Scholar 

  48. Zhao, Y. & Potter, S. S. Functional specificity of the Hoxa13 homeobox. Development 128, 3197–3207 (2001).

    CAS  PubMed  Google Scholar 

  49. Branford, W. W., Benson, G. V., Ma, L., Maas, R. L. & Potter, S. S. Characterization of Hoxa-10/Hoxa-11 transheterozygotes reveals functional redundancy and regulatory interactions. Dev. Biol. 224, 373–387 (2000).

    CAS  PubMed  Google Scholar 

  50. Taylor, H. S., Vanden Heuvel, G. B. & Igarashi, P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol. Reprod. 57, 1338–1345 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Benson, G. V. et al. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122, 2687–2696 (1996). This study shows that a Hox gene is involved in patterning the anterior–posterior axis of the female reproductive tract.

    CAS  PubMed  Google Scholar 

  53. Miller, C. & Sassoon, D. A. Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development 125, 3201–3211 (1998). This paper nicely describes the function of Wnt7a in the differentiation of the oviduct and uterus along both the anterior–posterior and lateral axes.

    CAS  PubMed  Google Scholar 

  54. Miller, C., Degenhardt, K. & Sassoon, D. A. Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis. Nature Genet. 20, 228–230 (1998). This study points to phenotypic similarities between the uterus of Wnt7a -null mutants and those of prenatally DES-treated wild-type animals. The authors show that prenatal DES treatment inhibits Wnt7a expression in the uterine epithelium.

    CAS  PubMed  Google Scholar 

  55. Mittendorf, R. Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology 51, 435–445 (1995).

    CAS  PubMed  Google Scholar 

  56. Ma, L., 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 the synthetic estrogen diethylstilbestrol (DES). Dev. Biol. 197, 141–154 (1998).

    CAS  PubMed  Google Scholar 

  57. Block, K., Kardana, A., Igarashi, P. & Taylor, H. S. In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system. FASEB J. 14, 1101–1108 (2000).

    CAS  PubMed  Google Scholar 

  58. Lindner, T. H. et al. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1β. Hum. Mol. Genet. 8, 2001–2008 (1999).

    CAS  PubMed  Google Scholar 

  59. Bingham, C. et al. Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1β mutations. Kidney Int. 61, 1243–1251 (2002).

    CAS  PubMed  Google Scholar 

  60. Coffinier, C., Barra, J., Babinet, C. & Yaniv, M. Expression of the vHNF1/HNF1β homeoprotein gene during mouse organogenesis. Mech. Dev. 89, 211–213 (1999).

    CAS  PubMed  Google Scholar 

  61. Reber, M. & Cereghini, S. Variant hepatocyte nuclear factor 1 expression in the mouse genital tract. Mech. Dev. 100, 75–8 (2001).

    CAS  PubMed  Google Scholar 

  62. Bai, Y., Pontoglio, M., Hiesberger, T., Sinclair, A. M. & Igarashi, P. Regulation of kidney-specific Ksp-cadherin gene promoter by hepatocyte nuclear factor-1β. Am. J. Physiol. Renal Physiol. 283, 839–851 (2002).

    Google Scholar 

  63. Wertz, K. & Herrmann, B. G. Kidney-specific cadherin (cdh16) is expressed in embryonic kidney, lung, and sex ducts. Mech. Dev. 84, 185–188 (1999).

    CAS  PubMed  Google Scholar 

  64. Coffinier, C., Thepot, D., Babinet, C., Yaniv, M. & Barra, J. Essential role for the homeoprotein vHNF1/HNF1β in visceral endoderm differentiation. Development 126, 4785–4794 (1999).

    CAS  PubMed  Google Scholar 

  65. Barbacci, E. et al. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 126, 4795–4805 (1999).

    CAS  PubMed  Google Scholar 

  66. Coffinier, C. et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β. Development 129, 1829–1838 (2002).

    CAS  PubMed  Google Scholar 

  67. David, A. et al. Hydrometrocolpos and polydactyly: a common neonatal presentation of Bardet–Biedl and McKusick–Kaufman syndromes. J. Med. Genet. 36, 599–603 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Stone, D. L. et al. Mutation of a gene encoding a putative chaperonin causes McKusick–Kaufman syndrome. Nature Genet. 25, 79–82 (2000).

    CAS  PubMed  Google Scholar 

  69. Belville, C., Josso, N. & Picard, J. Y. Persistence of Mullerian derivatives in males. Am J. Med. Genet. 89, 218–223 (1999).

    CAS  PubMed  Google Scholar 

  70. Urioste, M. et al. Persistence of mullerian derivatives, lymphangiectasis, hepatic failure, postaxial polydactyly, renal and craniofacial anomalies. Am J. Med. Genet. 47, 494–503 (1993).

    CAS  PubMed  Google Scholar 

  71. Hummel, K. P. Hypodactyly, a semidominant lethal mutation in mice. J. Hered. 61, 219–220 (1970).

    CAS  PubMed  Google Scholar 

  72. Mortlock, D. P., Post, L. C. & Innis, J. W. The molecular basis of hypodactyly (Hd): a deletion in Hoxa 13 leads to arrest of digital arch formation. Nature Genet. 13, 284–289 (1996).

    CAS  PubMed  Google Scholar 

  73. 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 (1996).

    CAS  PubMed  Google Scholar 

  74. Post, L. C., Margulies, E. H., Kuo, A. & Innis, J. W. Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein. Dev. Biol. 217, 290–300 (2000).

    CAS  PubMed  Google Scholar 

  75. Mortlock, D. P. & Innis, J. W. Mutation of HOXA13 in hand–foot–genital syndrome. Nature Genet. 15, 179–180 (1997). Identification of the involvement of a HOX gene, HOXA13 , in female reproductive-tract development in humans.

    CAS  PubMed  Google Scholar 

  76. Wawersik, S. & Maas, R. L. Vertebrate eye development as modeled in Drosophila. Hum. Mol. Genet. 9, 917–925 (2000).

    CAS  PubMed  Google Scholar 

  77. Capdevila, J. & Johnson, R. L. Hedgehog signaling in vertebrate and invertebrate limb patterning. Cell. Mol. Life Sci. 57, 1682–1694 (2000).

    CAS  PubMed  Google Scholar 

  78. Hirth, F. & Reichert, H. Conserved genetic programs in insect and mammalian brain development. Bioessays 21, 677–684 (1999).

    CAS  PubMed  Google Scholar 

  79. Newman, A. P. & Sternberg, P. W. Coordinated morphogenesis of epithelia during development of the Caenorhabditis elegans uterine–vulval connection. Proc. Natl Acad. Sci. USA 93, 9329–9333 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kornfeld, K. Vulval development in Caenorhabditis elegans. Trends Genet. 13, 55–61 (1997).

    CAS  PubMed  Google Scholar 

  81. Newman, A. P., Acton, G. Z., Hartwieg, E., Horvitz, H. R. & Sternberg, P. W. The lin-11 LIM domain transcription factor is necessary for morphogenesis of C. elegans uterine cells. Development 126, 5319–5326 (1999).

    CAS  PubMed  Google Scholar 

  82. Chamberlin, H. M. et al. The PAX gene egl-38 mediates developmental patterning in Caenorhabditis elegans. Development 124, 3919–3928 (1997).

    CAS  PubMed  Google Scholar 

  83. Maloof, J. N. & Kenyon, C. The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling. Development 125, 181–190 (1998).

    CAS  PubMed  Google Scholar 

  84. Gleason, J. E., Korswagen, H. C. & Eisenmann, D. M. Activation of Wnt signaling bypasses the requirement for RTK/Ras signaling during C. elegans vulval induction. Genes Dev. 16, 1281–1290 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Eisenmann, D. M., Maloof, J. N., Simske, J. S., Kenyon, C. & Kim, S. K. The β-catenin homologue BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development. Development 125, 3667–3680 (1998).

    CAS  PubMed  Google Scholar 

  86. Hoier, E. F., Mohler, W. A., Kim, S. K. & Hajnal, A. The Caenorhabditis elegans APC-related gene apr-1 is required for epithelial cell migration and Hox gene expression. Genes Dev. 14, 874–886 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Hogan, B. L. & Kolodziej, P. A. Organogenesis: molecular mechanisms of tubulogenesis. Nature Rev. Genet. 3, 513–523 (2002).

    CAS  PubMed  Google Scholar 

  88. Lubarsky, B. & Krasnow, M. A. Tube morphogenesis: making and shaping biological tubes. Cell 112, 19–28 (2003).

    CAS  PubMed  Google Scholar 

  89. Gruenwald, P. The relation of the growing Mullerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat. Rec. 81, 1–19 (1941).

    Google Scholar 

  90. Igarashi, P. et al. Ksp-cadherin gene promoter. II. Kidney-specific activity in transgenic mice. Am. J. Physiol. 277, 599–610 (1999).

    Google Scholar 

  91. Shao, X., Somlo, S. & Igarashi, P. Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. J. Am. Soc. Nephrol. 13, 1837–1846 (2002).

    CAS  PubMed  Google Scholar 

  92. Shao, X., Johnson, J. E., Richardson, J. A., Hiesberger, T. & Igarashi, P. A minimal Ksp-cadherin promoter linked to a green fluorescent protein reporter gene exhibits tissue-specific expression in the developing kidney and genitourinary tract. J. Am. Soc. Nephrol. 13, 1824–1836 (2002).

    CAS  PubMed  Google Scholar 

  93. Nef, S. & Parada, L. F. Hormones in male sexual development. Genes Dev. 14, 3075–3086 (2000). This review nicely describes how male development is regulated by testis-secreted hormones, including testosterone, MIS and Insl3.

    CAS  PubMed  Google Scholar 

  94. Forsberg, J. G. Cervicovaginal epithelium: its origin and development. Am. J. Obstet. Gynecol. 115, 1025–1043 (1973).

    CAS  PubMed  Google Scholar 

  95. Cunha, G. R. The dual origin of vaginal epithelium. Am. J. Anat. 143, 387–392 (1975).

    CAS  PubMed  Google Scholar 

  96. Drews, U., Sulak, O. & Schenck, P. A. Androgens and the development of the vagina. Biol. Reprod. 67, 1353–1359 (2002).

    CAS  PubMed  Google Scholar 

  97. Carroll, T. J. & Vize, P. D. Synergism between Pax-8 and lim-1 in embryonic kidney development. Dev. Biol. 214, 46–59 (1999).

    CAS  PubMed  Google Scholar 

  98. Roberts, L. M., Hirokawa, Y., Nachtigal, M. W. & Ingraham, H. A. Paracrine-mediated apoptosis in reproductive tract development. Dev. Biol. 208, 110–122 (1999).

    CAS  PubMed  Google Scholar 

  99. Zhao, Y. & Potter, S. S. Functional comparison of the Hoxa 4, Hoxa 10, and Hoxa 11 homeoboxes. Dev. Biol. 244, 21–36 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. Dai, X. et al. The ovo gene required for cuticle formation and oogenesis in flies is involved in hair formation and spermatogenesis in mice. Genes Dev. 12, 3452–3463 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Katsanis, N. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nature Genet. 26, 67–70 (2000).

    CAS  PubMed  Google Scholar 

  103. Slavotinek, A. M. et al. Mutations in MKKS cause Bardet–Biedl syndrome. Nature Genet. 26, 15–16 (2000).

    CAS  PubMed  Google Scholar 

  104. Griffin, J. E., Edwards, C., Madden, J. D., Harrod, M. J. & Wilson, J. D. Congenital absence of the vagina. The Mayer–Rokitansky–Kuster–Hauser syndrome. Ann. Intern. Med. 85, 224–236 (1976).

    CAS  PubMed  Google Scholar 

  105. Duncan, P. A., Shapiro, L. R., Stangel, J. J., Klein, R. M. & Addonizio, J. C. The MURCS association: Mullerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia. J. Pediatr. 95, 399–402 (1979).

    CAS  PubMed  Google Scholar 

  106. van Haelst, M. M. et al. Lymphangiectasia with persistent Mullerian derivatives: confirmation of autosomal recessive Urioste syndrome. Am. J. Med. Genet. 104, 65–68 (2001).

    CAS  PubMed  Google Scholar 

  107. Bellini, C. et al. Persistence of Mullerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome. Am. J. Med. Genet. 104, 69–74 (2001).

    CAS  PubMed  Google Scholar 

  108. Footz, T. K. et al. Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice: a search for candidate genes at or near the human chromosome 22 pericentromere. Genome Res. 11, 1053–1070 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Fryns, J. P., Moerman, F., Goddeeris, P., Bossuyt, C. & Van den Berghe, H. A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum. Genet. 50, 65–70 (1979).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Renfree for helpful comments. This work was supported by a National Institutes of Health grant to R.R.B.

Author information

Authors and Affiliations

  1. Baylor College of Medicine and Department of Molecular Genetics, Program in Developmental Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Akio Kobayashi & Richard R. Behringer

Authors
  1. Akio Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard R. Behringer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard R. Behringer.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Related links

Related links

DATABASES

FlyBase

ems

prd

wg

LocusLink

AMH

Ar

Bmpr1a

Emx2

Hoxa9

Hoxa10

Hoxa11

Hoxa13

Hoxd13

Lhx1

Ltap

MKKS

Mmp2

Nr0b1

Nr5a1

Pax2

Pax8

RARα1

RARβ2

RARγ

RXRα1

Sox9

Sry

TCF2

Wnt4

Wnt7a

Wt1

OMIM

cryptorchidism

Hand–foot–genital syndrome

maturity-onset diabetes of the young type 5

Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome

McKusick–Kaufman syndrome

Müllerian aplasia

MURCS association

Persistent Müllerian duct syndrome

postaxial polydactyly

Urioste syndrome

WormBase

apr-1

bar-1

egl-38

lin-11

lin-39

mab-5

Glossary

AGENESIS

A condition in which a body part is absent or does not develop completely.

ATRESIA

A condition in which an opening or passage for the tracts of the body is absent or closed.

SEPTATION

Refers to the state of being divided internally by a partition or partitions. In the female reproductive tract, septation is observed longitudinally or transversely.

INTERMEDIATE MESODERM

A region of the embryonic mesoderm that forms the urogenital system, including the kidneys, gonads and their tracts.

MESONEPHRIC DUCT

A tubule that forms by posterior extension of the pronephric duct and differentiates into the urinary and male reproductive tract: the Wolffian duct.

PARAMESONEPHRIC DUCT

A tubule that forms parallel to the mesonephric duct and differentiates into the female reproductive tract: the Müllerian duct.

PAIR-RULE GENE

A class of segmentation gene that determines segments along the anterior–posterior axis. The expression of pair-rule genes in a pattern of seven stripes that are perpendicular to the axis is regulated by another class of segmentation genes: the gap genes.

PRONEPHROS

The first kidney that appears in the embryo at the anterior end of the nephric duct. This is a transitional organ that subsequently degenerates during embryogenesis and is thought to be non-functional in mammals.

CHIMAERA ASSAY

A technique that assesses the mode of action of gene products by generating animals from a mixture of cells that are derived from two or more genetically distinct animals.

CELL-AUTONOMOUSLY

A mode of gene effect that is restricted to the cell in which the gene is expressed.

SEGMENT-POLARITY GENES

Segmentation genes that are required for patterning the body along the anterior–posterior axis. They are expressed in a pattern of 14 stripes at the onset of gastrulation and following the expression of pair-rule genes.

LEYDIG CELL

Interstitial mesenchymal cells of the mammalian testis that are involved in the synthesis of testosterone.

COELOMIC EPITHELIUM

An epithelial tissue that lines the surface of the body wall and abdominal organs.

EPIDIDYMIS

(Plural epididymides). The distal portion of the male reproductive tract that receives the sperm from the testis.

VAS DEFERENS

(Plural vas deferentia). The proximal portion of the male reproductive tract through which the sperm travels from the epididymis to the urethra.

MESONEPHROS

The second kidney that forms next to the pronephros posteriorly during embryogenesis. In mammals, this is a transient embryonic organ that subsequently degenerates but is thought to be functional. The urinary function is postnatally taken over by the metanephros.

CLOACA

The terminal end of the hindgut before division into the rectum and urogenital sinus. The dorsal part of the cloaca differentiates into the rectum and anal canal, and the ventral part differentiates into the urogenital sinus.

PLANAR-CELL POLARITY

The polarity of epithelial cells in the plane of the epithelium, which is orthogonal to their apical–basal axis.

SERTOLI CELLS

Tall columnar epithelial cells of the mammalian testis that are involved in the synthesis of Müllerian-inhibiting substance.

VIRILIZE

(Masculinize). To produce or cause male sexual characteristics.

PARACRINE

A form of cell–cell communication that depends on a secreted substance that acts over a short distance and does not enter the circulation.

AUTOCRINE

A mode of action of a secreted substance by which it affects the cell that secretes it.

ANIMAL-CAP ASSAY

An experimental system to study inductive interactions in the early embryogenesis of urodele amphibians and, subsequently, Xenopus. The animal cap of the blastula can respond to the appropriate inductive signal or transgene expression to produce a range of differentiated tissues.

MATRIX METALLOPROTEINASES

A family of proteinases that modify the extracellular matrix and require a metal in the catalytic process.

AFFYMETRIX GENE-CHIP ANALYSIS

The examination of gene-expression profiles by the high-density array of single-stranded DNA nucleotides.

HOX CLUSTERS

A group of linked regulatory homeobox genes that are involved in patterning the animal body axis during development. Homeobox genes are defined as those that contain an 180-base-pair sequence that encodes a DNA-binding helix–lturn–helix motif (a homeodomain).

HOMEOTIC TRANSFORMATION

When one embryonic axial segment alters its identity to that of another.

STENOSIS

A narrowing or obstruction of the opening or channel of a tract, which prevents the normal flow through it.

PARALOGUE

A homologous gene that originates by gene duplication.

VAGINAL FORNIX

(Plural vaginal fornices). An anatomical recess that is formed by the projection of the cervix into the upper part of the vagina. There are four fornices in a female: the anterior fornix, the posterior fornix and two lateral fornices.

HYDROMETROCOLPOS

The distension of the uterus and vagina by the accumulation of secreted fluid; this usually reflects a mechanical obstruction.

LYMPHANGIECTASIA

Dilation of the lymphatic vessels that is caused by lymphatic damage, which leads to the blockage of local lymphatic drainage.

HYPOSPADIAS

A congenital defect in which the urethra opens abnormally on the ventral side of the penis, rather than at the distal tip of the glans.

DOMINANT-NEGATIVE

A form of mutation that interferes with the function of its wild-type gene product.

CRE/LOXP

A site-specific recombination system that is derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which can lead to the excision of the intervening sequence when two loxP sites have the same orientation on the same DNA strand.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, A., Behringer, R. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet 4, 969–980 (2003). https://doi.org/10.1038/nrg1225

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1225

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