How to cite this WIREs title:
WIREs Dev Biol

Impact Factor: 3.754

The cell biology and molecular genetics of Müllerian duct development

Advanced Review

Zahida Yesmin Roly, Brendan Backhouse, Andrew Cutting, Tiong Yang Tan, Andrew H. Sinclair, Katie L. Ayers, Andrew T. Major, Craig A. Smith

Published Online: Jan 19 2018

DOI: 10.1002/wdev.310

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

The Müllerian ducts are part of the embryonic urogenital system. They give rise to mature structures that serve a critical function in the transport and development of the oocyte and/or embryo. In most vertebrates, both sexes initially develop Müllerian ducts during embryogenesis, but they regress in males under the influence of testis‐derived Anti‐Müllerian Hormone (AMH). A number of regulatory factors have been shown to be essential for proper duct development, including Bmp and Wnt signaling molecules, together with homeodomain transcription factors such as PAX2 and LIM1. Later in development, the fate of the ducts diverges between males and females and is regulated by AMH and Wnt signaling molecules (duct regression in males) and Hox genes (duct patterning in females). Most of the genes and molecular pathways known to be involved in Müllerian duct development have been elucidated through animal models, namely, the mouse and chicken. In addition, genetic analysis of humans with reproductive tract disorders has further defined molecular mechanisms of duct formation and differentiation. However, despite our current understanding of Müllerian duct development, some questions remain to be answered at the molecular genetic level. This article is categorized under: Early Embryonic Development > Development to the Basic Body Plan

HOX gene expression domains and patterning of the mammalian female reproductive tract. A subset of the HOXA cluster is expressed in a linear series along the length of the embryonic Müllerian duct (mouse studies). These expression domains correlate with subsequent regional differentiation of the ducts into fallopian tubes, fused uterus, cervix and vagina. (Reprinted with permission from Lynch et al. (). Copyright 2004 The Royal Society) Additional data from Du and Taylor ()

[ Normal View | Magnified View ]

Fate of the Müllerian duct in males and females. In both sexes, PAX2 and LIM1 are expressed during duct specification and elongation. These genes directly or indirectly regulate the expression of WNT7A in the Müllerian duct epithelium (MDE). WNT7A can activate expression of AMHR2 (AMH type II receptor) in the Müllerian duct mesenchyme (MDM). WNT4 is also expressed in the MDM. The AMH type I receptors (ALK2/3/6) also play a role in AMH signaling. Only in males, AMH secreted by the developing testis binds to AMHR2 to recruit type I receptors, and initiate intracellular Smad signaling, leading to activation of metalloproteases, apoptosis and duct regression. In females, lack of foetal AMH allows further duct development rather than regression. WNT7A can activate Hox genes involved in duct differentiation

[ Normal View | Magnified View ]

Genetic regulation of Müllerian duct (MD) specification, invagination and elongation, based on data from chicken and mouse embryos. (Reprinted with permission from Atsuta and Takahashi (). Copyright 2016 The Company of Biologists Ltd) Bmp signaling induces PAX2 expression in the cranial coelomic epithelium (orange) adjacent to the Wolffian duct (WD). BMP/PAX2 then activate Fgf signaling (blue) in the Müllerian surface epithelium (MSE). This then triggers LIM1 expression in the MSE (purple). Cells from the MSE (and possibly the mesonephros) give rise to the underlying Müllerian duct mesenchyme (MDM) which requires WNT4 expression (green). PAX2/LIM1‐positive MSE cells undergo invagination to from the Müllerian duct epithelium (MDE). WNT9B derived from the WD is required for duct elongation (red)

[ Normal View | Magnified View ]

The widely accepted three phase model of Müllerian duct development in vertebrate embryos, based on data from mouse and chicken. Only one side of the urogenital system is shown (dorsal view). (a) The Müllerian duct forms in a craniocaudal direction. During phase 1 (specification), Müllerian precursor cells are specified in the surface epithelium (Müllerian surface epithelium, MSE) at the cranial pole of the mesonephros (embryonic kidney). During phase 2 (invagination), these cells become “mesoepithelial” and invaginate in a caudal direction, moving between mesenchyme (the Müllerian duct mesenchyme, MDM). During phase 3, invaginating cells form the Müllerian Duct Epithelium (MDE) make contract with the Wolffian duct and the duct elongates caudally, eventually fusing with the urogenital sinus. (b) Müllerian invagination and elongation in the chicken embryo, stained for expression of the duct marker, Lim1. (c) Schematic cross‐section shows Wolffian and Müllerian ducts in the transverse plane. The Müllerian duct has three components, from the outer to inner surface: the MSE, the MDM and the MDE. (d) Cross section of Lim1‐expressing chicken stage 28 Müllerian duct

[ Normal View | Magnified View ]

Schematic view of urogenital system development in humans. (a) At the undifferentiated phase, the gonads develop on the ventromedial surface of the mesonephric kidneys. Two pairs of ducts form, the Wolffian (mesonephric) ducts and the Müllerian (paramesonephric) ducts. (b) Later in development, the action of AMH in males leads to Müllerian duct regression, while testosterone stimulates differentiation of the Wolffian ducts into male structures (vas deferens, epididymis and seminal vesicles). In the female, lack of these hormones leads to Müllerian duct differentiation into female structures (fallopian tubes) and regression of the Wolffian ducts. The mesonephros regresses in both sexes. (c) By birth, the paired testes and associated male ducts descend into the scrotum. In females, the fallopian tubes fuse caudally, giving rise to the uterus and upper portion of the vagina. (Bladder omitted in the female for clarity)

[ Normal View | Magnified View ]

References

Andrews,, J. E., Smith,, C. A., & Sinclair,, A. H. (1997). Sites of estrogen receptor and aromatase expression in the chicken embryo. General and Comparative Endocrinology, 108(2), 182–190. https://doi.org/10.1006/gcen.1997.6978
Arango,, N. A., Szotek,, P. P., Manganaro,, T. F., Oliva,, E., Donahoe,, P. K., & Teixeira,, J. (2005). Conditional deletion of beta‐catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Developmental Biology, 288(1), 276–283. https://doi.org/10.1016/j.ydbio.2005.09.045
Atsuta,, Y., & Takahashi,, Y. (2016). Early formation of the Mullerian duct is regulated by sequential actions of BMP/Pax2 and FGF/Lim1 signaling. Development, 143(19), 3549–3559. https://doi.org/10.1242/dev.137067
Austin,, H. B. (1989). The effects of estradiol and testosterone on mullerian‐duct regression in the American alligator (Alligator mississippiensis). General and Comparative Endocrinology, 76(3), 461–472.
Ayers,, K. L., Cutting,, A. D., Roeszler,, K. N., Sinclair,, A. H., & Smith,, C. A. (2015). DMRT1 is required for Mullerian duct formation in the chicken embryo. Developmental Biology, 400(2), 224–236. https://doi.org/10.1016/j.ydbio.2015.02.001
Behringer,, R. R., Cate,, R. L., Froelick,, G. J., Palmiter,, R. D., & Brinster,, R. L. (1990). Abnormal sexual development in transgenic mice chronically expressing mullerian inhibiting substance. Nature, 345(6271), 167–170. https://doi.org/10.1038/345167a0
Behringer,, R. R., Finegold,, M. J., & Cate,, R. L. (1994). Mullerian‐inhibiting substance function during mammalian sexual development. Cell, 79(3), 415–425. https://doi.org/10.1016/0092-8674(94)90251-8
Belville,, C., Josso,, N., & Picard,, J. Y. (1999). Persistence of Mullerian derivatives in males. American Journal of Medical Genetics, 89(4), 218–223.
Belville,, C., Maréchal,, J. D., Pennetier,, S., Carmillo,, P., Masgrau,, L., Messika‐Zeitoun,, L., … di Clemente,, N. (2009). Natural mutations of the anti‐Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport. Human Molecular Genetics, 18, 3002–3013.
Benson,, G. V., Lim,, H., Paria,, B. C., Satokata,, I., Dey,, S. K., & Maas,, R. L. (1996). Mechanisms of reduced fertility in Hoxa‐10 mutant mice: Uterine homeosis and loss of maternal Hoxa‐10 expression. Development, 122(9), 2687–2696.
Biason‐Lauber,, A., De Filippo,, G., Konrad,, D., Scarano,, G., Nazzaro,, A., & Schoenle,, E. J. (2007). WNT4 deficiency—a clinical phenotype distinct from the classic Mayer‐Rokitansky‐Kuster‐Hauser syndrome: A case report. Human Reproduction, 22(1), 224–229. https://doi.org/10.1093/humrep/del360
Biason‐Lauber,, A., Konrad,, D., Navratil,, F., & Schoenle,, E. J. (2004). A WNT4 mutation associated with Mullerian‐duct regression and virilization in a 46, XX woman. The New England Journal of Medicine, 351(8), 792–798. https://doi.org/10.1056/NEJMoa040533
Bingham,, C., Ellard,, S., Cole,, T. R., Jones,, K. E., Allen,, L. I., Goodship,, J. A., … Hattersley,, A. T. (2002). Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor‐1beta mutations. Kidney International, 61(4), 1243–1251. https://doi.org/10.1046/j.1523-1755.2002.00272.x
Bishop‐Calame,, S. (1966). Experimental study of the organogenesis of the urogenital system of the chicken embryo. Archives d`Anatomie Microscopique et de Morphologie Expérimentale, 55(2), 215–309.
Block,, K., Kardana,, A., Igarashi,, P., & Taylor,, H. S. (2000). In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing Mullerian system. The FASEB Journal, 14(9), 1101–1108.
Bouchard,, M., Souabni,, A., Mandler,, M., Neubuser,, A., & Busslinger,, M. (2002). Nephric lineage specification by Pax2 and Pax8. Genes %26 Development, 16(22), 2958–2970. https://doi.org/10.1101/gad.240102
Branford,, W. W., Benson,, G. V., Ma,, L., Maas,, R. L., & Potter,, S. S. (2000). Characterization of Hoxa‐10/Hoxa‐11 transheterozygotes reveals functional redundancy and regulatory interactions. Developmental Biology, 224(2), 373–387. https://doi.org/10.1006/dbio.2000.9809
Burel,, A., Mouchel,, T., Odent,, S., Tiker,, F., Knebelmann,, B., Pellerin,, I., & Guerrier,, D. (2006). Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). Journal of Negative Results in Biomedicine, 5, 4. https://doi.org/10.1186/1477-5751-5-4
Carroll,, T. J., Park,, J. S., Hayashi,, S., Majumdar,, A., & McMahon,, A. P. (2005). Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Developmental Cell, 9(2), 283–292. https://doi.org/10.1016/j.devcel.2005.05.016
Cermik,, D., Selam,, B., & Taylor,, H. S. (2003). Regulation of HOXA‐10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism, 88(1), 238–243. https://doi.org/10.1210/jc.2002-021072
Cheng,, Z., Zhu,, Y., Su,, D., Wang,, J., Cheng,, L., Chen,, B., … Cao,, Y. (2011). A novel mutation of HOXA10 in a Chinese woman with a Mullerian duct anomaly. Human Reproduction, 26(11), 3197–3201. https://doi.org/10.1093/humrep/der290
Chiga,, M., Ohmori,, T., Ohba,, T., Katabuchi,, H., & Nishinakamura,, R. (2014). Preformed Wolffian duct regulates Mullerian duct elongation independently of canonical Wnt signaling or Lhx1 expression. The International Journal of Developmental Biology, 58(9), 663–668. https://doi.org/10.1387/ijdb.140261rn
Choussein,, S., Nasioudis,, D., Schizas,, D., & Economopoulos,, K. P. (2017). Mullerian dysgenesis: A critical review of the literature. Archives of Gynecology and Obstetrics, 295(6), 1369–1381. https://doi.org/10.1007/s00404-017-4372-2
Clarke,, T. R., Hoshiya,, Y., Yi,, S. E., Liu,, X., Lyons,, K. M., & Donahoe,, P. K. (2001). Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)‐like pathway mediated by ALK2 and induces SMAD6 expression. Molecular Endocrinology, 15(6), 946–959. https://doi.org/10.1210/mend.15.6.0664
Cutting,, A. D., Ayers,, K., Davidson,, N., Oshlack,, A., Doran,, T., Sinclair,, A. H., … Smith,, C. A. (2014). Identification, expression, and regulation of anti‐Mullerian hormone type‐II receptor in the embryonic chicken gonad. Biology of Reproduction, 90(5), 106. https://doi.org/10.1095/biolreprod.113.116491
Deutscher,, E., & Hung‐Chang Yao,, H. (2007). Essential roles of mesenchyme‐derived beta‐catenin in mouse Mullerian duct morphogenesis. Developmental Biology, 307(2), 227–236. https://doi.org/10.1016/j.ydbio.2007.04.036
di Clemente,, N., & Belville,, C. (2006). Anti‐Mullerian hormone receptor defect. Best Practice %26 Research. Clinical Endocrinology %26 Metabolism, 20(4), 599–610. https://doi.org/10.1016/j.beem.2006.09.004
di Clemente,, N., Josso,, N., Gouedard,, L., & Belville,, C. (2003). Components of the anti‐Mullerian hormone signaling pathway in gonads. Molecular and Cellular Endocrinology, 211(1–2), 9–14. https://doi.org/10.1016/j.mce.2003.09.005
Didier,, E. (1971). The Wolffian duct induces the formation of the ostium of the Mullerian duct: Demonstration in the chick embryo. Journal of Embryology and Experimental Morphology, 25(1), 115–129.
Dodd,, K. L., & Wibbels,, T. (2008). Estrogen inhibits caudal progression but stimulates proliferation of developing mullerian ducts in a turtle with temperature‐dependent sex determination. Comparative Biochemistry and Physiology. Part A Molecular %26 Integrative Physiology, 150(3), 315–319. https://doi.org/10.1016/j.cbpa.2008.04.002
Dohr,, G., & Tarmann,, T. (1984). Contacts between the Wolffian and Müllerian cells at the tip of the outgrowing Müllerian duct in rat embryos. Acta Anatomica, 120, 123–128.
Doi,, O., & Hutson,, J. M. (1988). Pretreatment of chick embryos with estrogen in ovo prevents Mullerian duct regression in organ culture. Endocrinology, 122(6), 2888–2891. https://doi.org/10.1210/endo-122-6-2888
Dougherty,, D. C., & Sanders,, M. M. (2005). Estrogen action: Revitalization of the chick oviduct model. Trends in Endocrinology and Metabolism, 16(9), 414–419. https://doi.org/10.1016/j.tem.2005.09.001
Du,, H., & Taylor,, H. S. (2004). Molecular regulation of Mullerian development by Hox genes. Annals of the New York Academy of Sciences, 1034, 152–165. https://doi.org/10.1196/annals.1335.018
Du,, H., & Taylor,, H. S. (2015). The role of Hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harbor Perspectives in Medicine, 6(1), a023002. https://doi.org/10.1101/cshperspect.a023002
Ekici,, A. B., Strissel,, P. L., Oppelt,, P. G., Renner,, S. P., Brucker,, S., Beckmann,, M. W., & Strick,, R. (2013). HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina. Gene, 518(2), 267–272. https://doi.org/10.1016/j.gene.2013.01.030
Frisen,, L., Lagerstedt,, K., Tapper‐Persson,, M., Kockum,, I., & Nordenskjold,, A. (2003). A novel duplication in the HOXA13 gene in a family with atypical hand‐foot‐genital syndrome. Journal of Medical Genetics, 40(4), e49–449.
Fujino,, A., Arango,, N. A., Zhan,, Y., Manganaro,, T. F., Li,, X., MacLaughlin,, D. T., & Donahoe,, P. K. (2009). Cell migration and activated PI3K/AKT‐directed elongation in the developing rat Mullerian duct. Developmental Biology, 325(2), 351–362. https://doi.org/10.1016/j.ydbio.2008.10.027
Gendron,, R. L., Paradis,, H., Hsieh‐Li,, H. M., Lee,, D. W., Potter,, S. S., & Markoff,, E. (1997). Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa‐11 mice. Biology of Reproduction, 56(5), 1097–1105.
George,, F. W., & Wilson,, J. D. (1994). Sex determination and differentiation (Vol. 1). New York, NY: Raven Press.
Goodman,, F. R., Bacchelli,, C., Brady,, A. F., Brueton,, L. A., Fryns,, J. P., Mortlock,, D. P., … Scambler,, P. J. (2000). Novel HOXA13 mutations and the phenotypic spectrum of hand‐foot‐genital syndrome. American Journal of Human Genetics, 67(1), 197–202. https://doi.org/10.1086/302961
Gouedard,, L., Chen,, Y. G., Thevenet,, L., Racine,, C., Borie,, S., Lamarre,, I., … di Clemente,, N. (2000). Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti‐Mullerian hormone and its type II receptor. The Journal of Biological Chemistry, 275(36), 27973–27978. https://doi.org/10.1074/jbc.M002704200
Griffin,, J. E., Edwards,, C., Madden,, J. D., Harrod,, M. J., & Wilson,, J. D. (1976). Congenital absence of the vagina. The Mayer‐Rokitansky‐Kuster‐Hauser syndrome. Annals of Internal Medicine, 85(2), 224–236.
Gruenwald,, P. (1941). The relation of the growing Müllerian duct to the Wolffian duct and its importance for the genesis of malformations. The Anatomical Record, 81(1), 1–19. https://doi.org/10.1002/ar.1090810102
Guioli,, S., Nandi,, S., Zhao,, D., Burgess‐Shannon,, J., Lovell‐Badge,, R., & Clinton,, M. (2014). Gonadal asymmetry and sex determination in birds. Sexual Development, 8(5), 227–242. https://doi.org/10.1159/000358406
Guioli,, S., Sekido,, R., & Lovell‐Badge,, R. (2007). The origin of the Mullerian duct in chick and mouse. Developmental Biology, 302(2), 389–398. https://doi.org/10.1016/j.ydbio.2006.09.046
Ha,, Y., Tsukada,, A., Saito,, N., Zadworny,, D., & Shimada,, K. (2008). Identification of differentially expressed genes involved in the regression and development of the chicken Mullerian duct. The International Journal of Developmental Biology, 52(8), 1135–1141. https://doi.org/10.1387/ijdb.072441yh
Hamburger,, V., & Hamilton,, H. L. (1951). A series of normal stages in the development of the chick embryo. Journal of Morphology, 88(1), 49–92.
Huang,, C. C., Orvis,, G. D., Kwan,, K. M., & Behringer,, R. R. (2014). Lhx1 is required in Mullerian duct epithelium for uterine development. Developmental Biology, 389(2), 124–136. https://doi.org/10.1016/j.ydbio.2014.01.025
Hutson,, J. M., Donahoe,, P. K., & MacLaughlin,, D. T. (1985). Steroid modulation of Mullerian duct regression in the chick embryo. General and Comparative Endocrinology, 57(1), 88–102.
Hutson,, J. M., Ikawa,, H., & Donahoe,, P. K. (1982). Estrogen inhibition of Mullerian inhibiting substance in the chick embryo. Journal of Pediatric Surgery, 17(6), 953–959.
Jacob,, M., Konrad,, K., & Jacob,, H. J. (1999). Early development of the Mullerian duct in avian embryos with reference to the human. An ultrastructural and immunohistochemical study. Cells, Tissues, Organs, 164(2), 63–81. https://doi.org/10.1159/000016644
Jamin,, S. P., Arango,, N. A., Mishina,, Y., Hanks,, M. C., & Behringer,, R. R. (2002). Requirement of Bmpr1a for Mullerian duct regression during male sexual development. Nature Genetics, 32(3), 408–410. https://doi.org/10.1038/ng1003
Jamin,, S. P., Arango,, N. A., Mishina,, Y., Hanks,, M. C., & Behringer,, R. R. (2003). Genetic studies of the AMH/MIS signaling pathway for Mullerian duct regression. Molecular and Cellular Endocrinology, 211(1–2), 15–19. https://doi.org/10.1016/j.mce.2003.09.006
Jeong,, J. W., Lee,, H. S., Franco,, H. L., Broaddus,, R. R., Taketo,, M. M., Tsai,, S. Y., … DeMayo,, F. J. (2009). Beta‐catenin mediates glandular formation and dysregulation of beta‐catenin induces hyperplasia formation in the murine uterus. Oncogene, 28(1), 31–40. https://doi.org/10.1038/onc.2008.363
Josso,, N. (1991). Anti‐Mullerian hormone. Baillière`s Clinical Endocrinology and Metabolism, 5(4), 635–654.
Josso,, N., Cate,, R. L., Picard,, J. Y., Vigier,, B., di Clemente,, N., Wilson,, C., … Boussin,, L. (1993). Anti‐Mullerian hormone: The Jost factor. Recent Progress in Hormone Research, 48, 1–59.
Josso,, N., di Clemente,, N., & Gouedard,, L. (2001). Anti‐Mullerian hormone and its receptors. Molecular and Cellular Endocrinology, 179(1–2), 25–32.
Josso,, N., Lamarre,, I., Picard,, J. Y., Berta,, P., Davies,, N., Morichon,, N., … Jeny,, R. (1993). Anti‐Mullerian hormone in early human development. Early Human Development, 33(2), 91–99.
Kastner,, P., Mark,, M., Ghyselinck,, N., Krezel,, W., Dupe,, V., Grondona,, J. M., & Chambon,, P. (1997). Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development, 124(2), 313–326.
Klattig,, J., & Englert,, C. (2007). The Mullerian duct: Recent insights into its development and regression. Sexual Development, 1(5), 271–278. https://doi.org/10.1159/000108929
Klattig,, J., Sierig,, R., Kruspe,, D., Besenbeck,, B., & Englert,, C. (2007). Wilms` tumor protein Wt1 is an activator of the anti‐Mullerian hormone receptor gene Amhr2. Molecular and Cellular Biology, 27(12), 4355–4364. https://doi.org/10.1128/MCB.01780-06
Kobayashi,, A., & Behringer,, R. R. (2003). Developmental genetics of the female reproductive tract in mammals. Nature Reviews. Genetics, 4(12), 969–980. https://doi.org/10.1038/nrg1225
Kobayashi,, A., Shawlot,, W., Kania,, A., & Behringer,, R. R. (2004). Requirement of Lim1 for female reproductive tract development. Development, 131(3), 539–549. https://doi.org/10.1242/dev.00951
Laronda,, M. M., Unno,, K., Ishi,, K., Serna,, V. A., Butler,, L. M., Mills,, A. A., … Kurita,, T. (2013). Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1‐mediated cell fate decision in the Mullerian duct epithelium. Developmental Biology, 381(1), 5–16. https://doi.org/10.1016/j.ydbio.2013.06.024
Ledig,, S., Brucker,, S., Barresi,, G., Schomburg,, J., Rall,, K., & Wieacker,, P. (2012). Frame shift mutation of LHX1 is associated with Mayer‐Rokitansky‐Kuster‐Hauser (MRKH) syndrome. Human Reproduction, 27(9), 2872–2875. https://doi.org/10.1093/humrep/des206
Ledig,, S., Schippert,, C., Strick,, R., Beckmann,, M. W., Oppelt,, P. G., & Wieacker,, P. (2011). Recurrent aberrations identified by array‐CGH in patients with Mayer‐Rokitansky‐Kuster‐Hauser syndrome. Fertility and Sterility, 95(5), 1589–1594. https://doi.org/10.1016/j.fertnstert.2010.07.1062
Lindner,, T. H., Njolstad,, P. R., Horikawa,, Y., Bostad,, L., Bell,, G. I., & Sovik,, O. (1999). 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‐1beta. Human Molecular Genetics, 8(11), 2001–2008.
Liu,, S., Gao,, X., Qin,, Y., Liu,, W., Huang,, T., Ma,, J., … Chen,, Z. J. (2015). Nonsense mutation of EMX2 is potential causative for uterus didelphysis: First molecular explanation for isolated incomplete Mullerian fusion. Fertility and Sterility, 103(3), 769–774 e762. https://doi.org/10.1016/j.fertnstert.2014.11.030
Lokmane,, L., Heliot,, C., Garcia‐Villalba,, P., Fabre,, M., & Cereghini,, S. (2010). vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis. Development, 137(2), 347–357. https://doi.org/10.1242/dev.042226
Londra,, L., Chuong,, F. S., & Kolp,, L. (2015). Mayer‐Rokitansky‐Kuster‐Hauser syndrome: A review. International Journal of Womens Health, 7, 865–870. https://doi.org/10.2147/IJWH.S75637
Lynch,, V. J., Roth,, J. J., Takahashi,, K., Dunn,, C. W., Nonaka,, D. F., Stopper,, G. F., & Wagner,, G. P. (2004). Adaptive evolution of HoxA‐11 and HoxA‐13 at the origin of the uterus in mammals. Proceedings of the Biological Sciences, 271(1554), 2201–2207. https://doi.org/10.1098/rspb.2004.2848
Ma,, L., Benson,, G. V., Lim,, H., Dey,, S. K., & Maas,, R. L. (1998). Abdominal B (AbdB) Hoxa genes: Regulation in adult uterus by estrogen and progesterone and repression in Mullerian duct by the synthetic estrogen diethylstilbestrol (DES). Developmental Biology, 197(2), 141–154. https://doi.org/10.1006/dbio.1998.8907
Ma,, W., Li,, Y., Wang,, M., Li,, H., Su,, T., Li,, Y., & Wang,, S. (2015). Associations of polymorphisms in WNT9B and PBX1 with Mayer‐Rokitansky‐Kuster‐Hauser syndrome in Chinese Han. PLoS ONE, 10(6), e0130202. https://doi.org/10.1371/journal.pone.0130202
Magro,, G., & Grasso,, S. (1995). Expression of cytokeratins, vimentin and basement membrane components in human fetal male Mullerian duct and perimullerian mesenchyme. Acta Histochemica, 97(1), 13–18. https://doi.org/10.1016/S0065-1281(11)80202-3
Mattsson,, A., Olsson,, J. A., & Brunstrom,, B. (2011). Activation of estrogen receptor alpha disrupts differentiation of the reproductive organs in chicken embryos. General and Comparative Endocrinology, 172(2), 251–259. https://doi.org/10.1016/j.ygcen.2011.03.010
Mendelsohn,, C., Lohnes,, D., Decimo,, D., Lufkin,, T., LeMeur,, M., Chambon,, P., & Mark,, M. (1994). Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development, 120(10), 2749–2771.
Mericskay,, M., Kitajewski,, J., & Sassoon,, D. (2004). Wnt5a is required for proper epithelial‐mesenchymal interactions in the uterus. Development, 131(9), 2061–2072. https://doi.org/10.1242/dev.01090
Miller,, C., & Sassoon,, D. A. (1998). Wnt‐7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development, 125(16), 3201–3211.
Minami,, N., & Iritani,, A. (1993). Role of the oviduct in the development of the mouse embryo. Molecular Reproduction and Development, 36(2), 279–281. https://doi.org/10.1002/mrd.1080360231
Mishina,, Y., Rey,, R., Finegold,, M. J., Matzuk,, M. M., Josso,, N., Cate,, R. L., & Behringer,, R. R. (1996). Genetic analysis of the Mullerian‐inhibiting substance signal transduction pathway in mammalian sexual differentiation. Genes %26 Development, 10(20), 2577–2587. https://doi.org/10.1101/gad.10.20.2577
Mishina,, Y., Whitworth,, D. J., Racine,, C., & Behringer,, R. R. (1999). High specificity of Mullerian‐inhibiting substance signaling in vivo. Endocrinology, 140(5), 2084–2088. https://doi.org/10.1210/endo.140.5.6705
Miyamoto,, N., Yoshida,, M., Kuratani,, S., Matsuo,, I., & Aizawa,, S. (1997). Defects of urogenital development in mice lacking Emx2. Development, 124(9), 1653–1664.
Morcel,, K., Watrin,, T., Pasquier,, L., Rochard,, L., Le Caignec,, C., Dubourg,, C., … Guerrier,, D. (2011). Utero‐vaginal aplasia (Mayer‐Rokitansky‐Kuster‐Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge‐like loci. Orphanet Journal of Rare Diseases, 6, 9. https://doi.org/10.1186/1750-1172-6-9
Mullen,, R. D., & Behringer,, R. R. (2014). Molecular genetics of Mullerian duct formation, regression and differentiation. Sexual Development, 8(5), 281–296. https://doi.org/10.1159/000364935
Nakajima,, T., Iguchi,, T., & Sato,, T. (2016). Retinoic acid signaling determines the fate of uterine stroma in the mouse Mullerian duct. Proceedings of the National Academy of Sciences of the United States of America, 113(50), 14354–14359. https://doi.org/10.1073/pnas.1608808113
Oka,, T., & Schimke,, R. T. (1969a). Interaction of estrogen and progesterone in chick oviduct development. I. Antagonistic effect of progesterone on estrogen‐induced proliferation and differentiation of tubular gland cells. Journal of Cell Biology, 41(3), 816–831.
Oka,, T., & Schimke,, R. T. (1969b). Interaction of estrogen and progesterone in chick oviduct development. II. Effects of estrogen and progesterone on tubular gland cell function. Journal of Cell Biology, 43(1), 123–137.
Oppelt,, P., Strissel,, P. L., Kellermann,, A., Seeber,, S., Humeny,, A., Beckmann,, M. W., & Strick,, R. (2005). DNA sequence variations of the entire anti‐Mullerian hormone (AMH) gene promoter and AMH protein expression in patients with the Mayer‐Rokitanski‐Kuster‐Hauser syndrome. Human Reproduction, 20(1), 149–157. https://doi.org/10.1093/humrep/deh547
Orvis,, G. D., & Behringer,, R. R. (2007). Cellular mechanisms of Mullerian duct formation in the mouse. Developmental Biology, 306(2), 493–504. https://doi.org/10.1016/j.ydbio.2007.03.027
Orvis,, G. D., Jamin,, S. P., Kwan,, K. M., Mishina,, Y., Kaartinen,, V. M., Huang,, S., … Behringer,, R. R. (2008). Functional redundancy of TGF‐beta family type I receptors and receptor‐Smads in mediating anti‐Mullerian hormone‐induced Mullerian duct regression in the mouse. Biology of Reproduction, 78(6), 994–1001. https://doi.org/10.1095/biolreprod.107.066605
Palmiter,, R. D., & Wrenn,, J. T. (1971). Interaction of estrogen and progesterone in chick oviduct development. 3. Tubular gland cell cytodifferentiation. The Journal of Cell Biology, 50(3), 598–615.
Park,, M. J., Kwak,, H. J., Lee,, H. C., Yoo,, D. H., Park,, I. C., Kim,, M. S., … Hong,, S. I. (2007). Nerve growth factor induces endothelial cell invasion and cord formation by promoting matrix metalloproteinase‐2 expression through the phosphatidylinositol 3‐kinase/Akt signaling pathway and AP‐2 transcription factor. The Journal of Biological Chemistry, 282(42), 30485–30496. https://doi.org/10.1074/jbc.M701081200
Parr,, B. A., & McMahon,, A. P. (1998). Sexually dimorphic development of the mammalian reproductive tract requires Wnt‐7a. Nature, 395(6703), 707–710. https://doi.org/10.1038/27221
Patnaik,, S. S., Brazile,, B., Dandolu,, V., Ryan,, P. L., & Liao,, J. (2015). Mayer‐Rokitansky‐Kuster‐Hauser (MRKH) syndrome: A historical perspective. Gene, 555(1), 33–40. https://doi.org/10.1016/j.gene.2014.09.045
Philibert,, A. B.‐L., Rouzier,, R., Pienkowski,, C., Paris,, F., Konrad,, D., Schoenle,, E., & Sultan,, C. (2008). Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: A French collaborative study. The Journal of Clinical Endocrinology and Metabolism, 93, 895–900.
Philibert,, P., Biason‐Lauber,, A., Gueorguieva,, I., Stuckens,, C., Pienkowski,, C., Lebon‐Labich,, B., … Sultan,, C. (2011). Molecular analysis of WNT4 gene in four adolescent girls with Mullerian duct abnormality and hyperandrogenism (atypical Mayer‐Rokitansky‐Kuster‐Hauser syndrome). Fertility and Sterility, 95(8), 2683–2686. https://doi.org/10.1016/j.fertnstert.2011.01.152
Post,, L. C., Margulies,, E. H., Kuo,, A., & Innis,, J. W. (2000). Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein. Developmental Biology, 217(2), 290–300. https://doi.org/10.1006/dbio.1999.9550
Prunskaite‐Hyyrylainen,, R., Skovorodkin,, I., Xu,, Q., Miinalainen,, I., Shan,, J., & Vainio,, S. J. (2016). Wnt4 coordinates directional cell migration and extension of the Mullerian duct essential for ontogenesis of the female reproductive tract. Human Molecular Genetics, 25(6), 1059–1073. https://doi.org/10.1093/hmg/ddv621
Pulkkinen,, M. O. (1995). Oviductal function is critical for very early human life. Annals of Medicine, 27(3), 307–310. https://doi.org/10.3109/07853899509002582
Roberts,, L. M., Visser,, J. A., & Ingraham,, H. A. (2002). Involvement of a matrix metalloproteinase in MIS‐induced cell death during urogenital development. Development, 129(6), 1487–1496.
Salehi,, P., Koh,, C. J., Pitukcheewanont,, P., Trinh,, L., Daniels,, M., & Geffner,, M. (2012). Persistent Mullerian duct syndrome: 8 new cases in Southern California and a review of the literature. Pediatric Endocrinology Reviews, 10(2), 227–233.
Sandbacka,, M., Laivuori,, H., Freitas,, E., Halttunen,, M., Jokimaa,, V., Morin‐Papunen,, L., … Aittomaki,, K. (2013). TBX6, LHX1 and copy number variations in the complex genetics of Mullerian aplasia. Orphanet Journal of Rare Diseases, 8, 125. https://doi.org/10.1186/1750-1172-8-125
Smith,, C. A., Roeszler,, K. N., Hudson,, Q. J., & Sinclair,, A. H. (2007). Avian sex determination: What, when and where? Cytogenetic and Genome Research, 117(1–4), 165–173. https://doi.org/10.1159/000103177
Song,, G., Seo,, H. W., Choi,, J. W., Rengaraj,, D., Kim,, T. M., Lee,, B. R., … Han,, J. Y. (2011). Discovery of candidate genes and pathways regulating oviduct development in chickens. Biology of Reproduction, 85(2), 306–314. https://doi.org/10.1095/biolreprod.110.089227
Stewart,, C. A., Wang,, Y., Bonilla‐Claudio,, M., Martin,, J. F., Gonzalez,, G., Taketo,, M. M., & Behringer,, R. R. (2013). CTNNB1 in mesenchyme regulates epithelial cell differentiation during Mullerian duct and postnatal uterine development. Molecular Endocrinology, 27(9), 1442–1454. https://doi.org/10.1210/me.2012-1126
Stoll,, R., Faucounau,, N., & Maraud,, R. (1990). Action of estradiol on Mullerian duct regression induced by treatment with norethindrone of female chick embryos. General and Comparative Endocrinology, 80(1), 101–106.
Stoll,, R., Ichas,, F., Faucounau,, N., & Maraud,, R. (1993a). Action of estradiol and tamoxifen on the Mullero‐regressive activity of the chick embryonic testis assayed in vivo by organotypic grafting. Anatomy and Embryology (Berlin), 187(4), 379–384.
Stoll,, R., Ichas,, F., Faucounau,, N., & Maraud,, R. (1993b). Action of estradiol and tamoxifen on the testis‐inducing activity of the chick embryonic testis grafted to the female embryo. Anatomy and Embryology (Berlin), 188(6), 587–592.
Suzuki,, Y., & Mclachlan,, J. A. (1979). Effects of sex‐hormones on Mullerian duct derivatives in the genital‐tract of male‐mice exposed prenatally to diethylstilbestrol (des). Biology of Reproduction, 20, A115–A115.
Tanwar,, P. S., Zhang,, L., Tanaka,, Y., Taketo,, M. M., Donahoe,, P. K., & Teixeira,, J. M. (2010). Focal Mullerian duct retention in male mice with constitutively activated beta‐catenin expression in the Mullerian duct mesenchyme. Proceedings of the National Academy of Sciences of the United States of America, 107(37), 16142–16147. https://doi.org/10.1073/pnas.1011606107
Taylor,, H. S., Vanden Heuvel,, G. B., & Igarashi,, P. (1997). A conserved Hox axis in the mouse and human female reproductive system: Late establishment and persistent adult expression of the Hoxa cluster genes. Biology of Reproduction, 57(6), 1338–1345.
Torres,, M., Gomez‐Pardo,, E., Dressler,, G. R., & Gruss,, P. (1995). Pax‐2 controls multiple steps of urogenital development. Development, 121(12), 4057–4065.
Utsch,, B., Becker,, K., Brock,, D., Lentze,, M. J., Bidlingmaier,, F., & Ludwig,, M. (2002). A novel stable polyalanine [poly(a)] expansion in the HOXA13 gene associated with hand‐foot‐genital syndrome: Proper function of poly(a)‐harbouring transcription factors depends on a critical repeat length? Human Genetics, 110(5), 488–494. https://doi.org/10.1007/s00439-002-0712-8
Vaillant,, S., Dorizzi,, M., Pieau,, C., & Richard‐Mercier,, N. (2001). Sex reversal and aromatase in chicken. The Journal of Experimental Zoology, 290(7), 727–740.
Vainio,, S., Heikkila,, M., Kispert,, A., Chin,, N., & McMahon,, A. P. (1999). Female development in mammals is regulated by Wnt‐4 signalling. Nature, 397(6718), 405–409. https://doi.org/10.1038/17068
Visser,, J. A., Olaso,, R., Verhoef‐Post,, M., Kramer,, P., Themmen,, A. P., & Ingraham,, H. A. (2001). The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling. Molecular Endocrinology, 15(6), 936–945. https://doi.org/10.1210/mend.15.6.0645
Warot,, X., Fromental‐Ramain,, C., Fraulob,, V., Chambon,, P., & Dolle,, P. (1997). 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(23), 4781–4791.
Waschk,, D. E., Tewes,, A. C., Romer,, T., Hucke,, J., Kapczuk,, K., Schippert,, C., … Ledig,, S. (2016). Mutations in WNT9B are associated with Mayer‐Rokitansky‐Kuster‐Hauser syndrome. Clinical Genetics, 89(5), 590–596. https://doi.org/10.1111/cge.12701
Wibbels,, T., Wilson,, C., & Crews,, D. (1999). Mullerian duct development and regression in a turtle with temperature‐dependent sex determination. Journal of Herpetology, 33(1), 149, 152. https://doi.org/10.2307/1565558

Society Partners

	Free online access to WIREs Developmental Biology is a member benefit. Learn More
	SDB Collaborative Resources
	Society for Developmental Biology Homepage

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts