Table of Contents  
Year : 2015  |  Volume : 17  |  Issue : 5  |  Page : 749-755

Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice

1 Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Wakayama, Japan
2 Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

Date of Web Publication26-Jun-2015

Correspondence Address:
Barry T Hinton
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1008-682X.155540

Rights and Permissions

The development of the Wolffian/epididymal duct is crucial for proper function and, therefore, male fertility. The development of the epididymis is complex; the initial stages form as a transient embryonic kidney; then the mesonephros is formed, which in turn undergoes extensive morphogenesis under the influence of androgens and growth factors. Thus, understanding of its full development requires a wide and multidisciplinary view. This review focuses on mouse models that display abnormalities of the Wolffian duct and mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to our understanding of clinical abnormalities in humans such as congenital anomalies of the kidney and urinary tract (CAKUT).

Keywords: epididymis; mesonephros; transgenic mice; Wolffian duct

How to cite this article:
Murashima A, Xu B, Hinton BT. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice. Asian J Androl 2015;17:749-55

How to cite this URL:
Murashima A, Xu B, Hinton BT. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice. Asian J Androl [serial online] 2015 [cited 2022 Dec 5];17:749-55. Available from:

This article was presented at the 6th International Conference on the Epididymis in Shanghai, Oct 31-Nov 3, 2014.

  Introduction Top

Understanding the mechanisms that regulate the development of the Wolffian duct (WD) is important because disruption of epididymal function may arise as a consequence of its abnormal development. Very little is known of either the process of WD development or the nature and causes of congenital defects that lead to male infertility. For example, it is clear that an undeveloped initial segment of the epididymis leads to male infertility [1],[2] and considering that the human epididymis has an initial segment-like epithelium, [3] it is important to at least understand the development of this region. There are three developmental processes that are considered to be important during the development of the WD: (1) mesonephros formation, (2) stabilization of the ductal system and further growth, (3) postnatal differentiation ([Figure 1]). Each process is dependent upon developmental factors as shown by WD phenotypic mice carrying mutations of each factor.
Figure 1: Schematic diagram of mouse Wolffian/epididymal duct development. ( a-c ) The origin of the epididymis is the intermediate mesoderm. Spatiotemporally distinct intermediate mesoderm at E8.5 gives rise to the WD and metanephric mesenchyme.37 The anterior intermediate mesoderm, which gives rise to the pronephros and the whole WD, is composed of Osr1-positive cells at E8.5. The posterior intermediate mesoderm, which gives rise to the metanephric mesenchyme, is positive for T at E9.5. The posterior intermediate mesoderm may correspond to axial progenitor cells, which serve as the source of the caudal body trunk.96,97 The WD begins to form from the anterior intermediate mesoderm at E8.5 and grows posteriorly reaching the urogenital sinus at E9.5.98 Meanwhile, the pronephros regresses through apoptosis.99 The WD induces the formation of mesonephric tubules from the mesenchyme (nephric cord) adjacent to the WD in a cranio-caudal manner. At the caudal end of the WD, the metanephros is initiated by ureteric bud formation through the interaction between WD epithelia and the metanephric mesenchyme at E10.5. ( d ) After gonadal sexual differentiation begins, the WD in the female embryo regresses from cranial to caudal while the WD in the male embryo is stabilized. The cranial set of mesonephric tubules connected to the WD is stabilized while the caudal set of mesonephric tubules regresses via apoptosis. ( e ) In the male embryo, the stabilized WD begins to coil from the cranial portion at E15.5. The duct continues to elongate and coil throughout development. ( f ) Ductal elongation and coiling continue after birth. The single-layered ductal epithelia undergo differentiation between P15 and P44. At the same time, the regions of the epididymis, initial segment, caput, corpus and cauda, become morphologically distinct. Sperm transport through the duct begins at approximately P35.59,68 IM: intermediate mesoderm; UGS: urogenital sinus; IS: initial segment.

Click here to view

This review focuses on mouse models that display abnormalities in WD or mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to understanding clinical abnormalities in humans. [Table 1] shows mutations of genes in mice that display Wolffian/epididymal duct phenotypes.
Table 1: Mouse models which show defects in WD/epididymal duct development

Click here to view

  Development of Wolffian/Epididymal Duct and Mouse Models Top

Mesonephros formation

During development, the nephric duct/Wolffian duct (WD) arises from the anterior, intermediate mesoderm, and extends caudally. [4] In the case of mouse, WD formation begins approximately on embryonic day (E) 8.5 and is completed by reaching the cloaca at E9.5 [5] ([Figure 1]a and b). As the WD elongates, it induces the formation of nephric tubules through a mesenchymal-epithelial transition process. The tubules form three kidney primordia: pronephros, mesonephros and metanephros [6] ([Figure 1]c). The pronephros and mesonephros are transient kidneys and degenerate soon after their formation. However, in the mesonephros, the WD and cranial mesonephric tubules (MT) are retained and give rise to the male reproductive tract including the epididymis and efferent ducts, respectively.

Because WD formation is crucial for kidney development in mammals, many mouse models that show abnormal WD or mesonephric development also display urogenital abnormalities. The paired domain transcription factors Pax2 and Pax8 are well-known inducers of the initial formation of the WD. [7],[8] The LIM-class homeobox gene Lim1 is required for the extension of the WD. [9],[10] Mice carrying a null mutation of Emx2, a mouse homologue of the Drosophila head gap gene empty spiracles (ems), display normal WD development until E10.5, but at later time points the duct degenerates, resulting in lack of a kidney and a failure of the reproductive tract to develop. [11] Mice carrying a null mutation of Gata3, which is a transcriptional target of Pax2 and Pax8, also show defects in WD initiation. [12]

Growth factors can differentially regulate gene expression especially through epithelial-mesenchymal interactions. Fibroblast growth factor (FGF) signaling is one of the well analyzed growth factor signaling events during mesonephric formation. Fgf8 encodes an FGF ligand, which is expressed in the intermediate mesoderm, and lack of its expression results in the absence of the cranial mesonephros and MTs. [13] FGF ligands bind and activate alternatively-spliced forms of four tyrosine kinase FGF receptors (FGFRs 1-4). [14] During mesonephric development, Fgfr1 is expressed in the mesenchyme while Fgfr2 is in the epithelium, maintaining the WD and mesonephric mesenchyme. [15] The function of FGFR2 in the WD epithelia is suggested to maintain the caudal part of the WD in the mesonephros by regulating cell proliferation. [16]

Wnt genes encode a family of secreted glycolipoproteins regulating multiple processes during development, including cell proliferation and cell polarity. Among the Wnt genes, Wnt9b is mainly expressed in the WD epithelium while Wnt7b is faintly expressed from E9.5 onward. In animals devoid of Wnt9b their MTs are absent, and the epididymis is lacking at birth despite the normal formation of the WD at E10.5. [17] β-catenin-dependent canonical WNT signaling, which mainly regulates cell proliferation and differentiation, is sufficient to rescue MT induction in Wnt9b null mice. On the other hand, during metanephric kidney development, attenuation of Wnt9b affects the planar cell polarity of the epithelium and lead to tubules with an increased diameter. [18] Further spatiotemporal analyses of epididymal development in this mutant would contribute to our understanding of this molecule in tubulogenesis and its maintenance.

The number of MTs differs between species, and their function as a secretory organ is observed in pigs and humans but not in mice. [19],[20],[21] The number of efferent ducts reaching the testis also differs between species. [22],[23] It is unclear whether there is a correlation between early MT number and the final number of efferent ducts observed in the adult. MT formation may resemble the formation of the renal nephron; both have the characteristic 'J' or 'S' shape during early development. The nephric tubule is formed through a mesenchymal-to-epithelial transition, and this cellular process is shared between mesonephric and metanephric tubules. Pax2/8, Emx2 and Lim1 are expressed in the condensed nephric cord and are required for tubulogenesis in addition to WD development. [7],[8],[9],[10],[11],[24] The Wilms' tumor suppressor gene Wt-1 and the homeobox gene Six1 are also expressed in the nephrogenic mesenchymal condensation throughout the nephrogenic cord. Mice lacking Wt-1 or Six1 lack caudal MTs while cranial MTs are intact. These observations indicate that the regulation of the cranial and caudal set of MTs is distinct. [25],[26],[27] Conversely, lack of the forkhead transcription factors Foxc1 and Foxc2, as well as Sonic hedgehog (Shh) expressed in the notochord or floor plate, results in supernumerary MT formation, suggesting suppressive effects of these genes on MT formation. [28],[29] It is important to uncover how the differential regulation of tubule formation and stabilization along the anterior-posterior axis of the nephrogenic cord is established.

The connection between the rete testis and efferent ducts is observed at E13.5, and testicular fluid transport is detected at the corresponding stage of the rat embryo. [30] The patterning of efferent duct formation is intriguing, but the manner by which they reach the testis is not clear. There are at least two hypotheses on how the efferent ducts could be formed: (1) that a subset of MTs branch and fuse with each other forming the characteristic network of ductules, (2) that branching morphogenesis does not occur and the characteristic network of ductules is formed by simple fusion of a subset of MTs. The latter hypothesis would seem more feasible than the first because of the presence of blind-ended tubules. These MTs only fuse to one other MT, leaving one end sealed, hence becoming blind-ended. Obviously, there must be considerable coordination between the fusion events that limit the number of MTs that can fuse [4],[5] resulting in the conus (2-3 fused MTs) and the single common ductule. [22] Identification of the genes and processes by which the formation and patterning of the efferent ducts occur is crucial, and the GUDMAP in situ hybridization database ( ) [31],[32] clearly shows some potential genes that may regulate their formation, e.g., collagen triple helix repeat containing 1(Cthrc1 ), cortexin 3 (Ctxn3) and laminin, alpha1 ( Lama1). Lunatic fringe (Lfng) is one of the mammalian fringe genes encoding a modifier of the notch receptor expressed in the developing WD, MTs and testis. [33],[34],[35] Lfng-null mice show partial bilateral blockage of the connection between the rete testis and the efferent ducts, indicating the involvement of notch signaling in establishing the rete testis-efferent duct boundary. [36]

The origins of nephron progenitor cells are suggested to differ between mesonephros and metanephros. [37] Metanephric mesenchyme is derived from a posterior immature caudal population, which is positive for Brachyury (T) expression, and persists in the posterior end of the embryo until body axis extension is complete ([Figure 1]a). On the other hand, the WD and at least part of the mesonephric mesenchyme arise from the anterior intermediate mesoderm, which is defined by Osr1 expression at E9.5 ([Figure 1]b). These recent studies may indicate that abnormal body axis extension affects the intermediate mesodermal cell fate. It is possible that disruption of the A-P body axis extension affects not only the metanephric mesenchyme but also the mesonephric mesenchymal distribution, and subsequently further male reproductive tract development. Conditionally-induced mutations of the planar cell polarity (PCP) pathway-related genes, Wnt5a, Ror2 and Vangl2, which are important for A-P body axis extension, demonstrate that insufficient A-P axis extension of the posterior intermediate mesoderm is correlated with urogenital tract abnormalities. [38] It is clear that more studies are needed to examine the early formation of the intermediate mesoderm and how this translates into development of the WD.

Stabilization of the ductal system and further growth: elongation and coiling

During embryogenesis, the mesonephros gives rise to a stable male reproductive tract whereas the mesonephros in the female regresses ( [Figure 1]d and 1e ). Androgens produced in the testis are a major factor regulating this stabilization. [39],[40],[41],[42] Following gonadal sex differentiation, the testis begins to produce the androgen, testosterone, at approximately E12.5. [43],[44] Unlike for other androgen-dependent organs, such as the prostate and seminal vesicle, it has been suggested that locally-produced, and not systemic androgen, from the testis is necessary for WD stabilization. [45] Indeed, fluorescence labeling of an androgen ligand shows that androgen is transported within the luminal fluid. [30] However, there are studies showing that testicular androgen delivered via the systemic circulation is sufficient to prevent WD regression. Subcutaneous testicular grafts stabilize the WD in female marsupial embryos. [46] Androgens act through the androgen receptor (AR), a member of the nuclear receptor superfamily. The expression of AR is mainly detected in the mesenchyme surrounding WD epithelia at E13.5 in the mouse. Tissue-specific Ar knockout (KO) analyses demonstrate that WD stabilization and coiling is induced in the absence of epithelial-expressed Ar, demonstrating the importance of Ar in the mesenchyme. [47] This finding is consistent with the observation from tissue recombination experiments on androgen-insensitive Testicular feminized (Tfm) mice. [48],[49] Several growth factors, including FGF and Epidermal growth factor (EGF), are suggested to mediate androgen functions in the prostate and WD. [50],[51],[52] However, the molecular mechanisms by which androgens regulate these genes in vivo are not known.

To create a long, highly-convoluted epididymal duct, the WD begins to elongate and coil from E15.5, following stabilization ( [Figure 1]e ). This process is also androgen-dependent, but growth factor signaling has been reported to regulate this elongation event. Tomaszewski et al. reported that Inhba, a subunit of both inhibins and activins, is a regional paracrine factor in mouse mesonephroi that controls coiling of the epithelium in the anterior WD. [53] Pkd1, whose mutation accounts for 85% of autosomal dominant polycystic kidney disease, and is a membrane-spanning glycoprotein involved in growth factor signaling transduction and cytoskeleton dynamics. Epithelial coiling is absent from the Pkd1 mutant. [54] In both mutations, epithelial cell proliferation is attenuated. Recently, mathematical modeling has suggested that epididymal tubule morphogenesis is dependent upon the cell proliferation area in the tubule and mechanical resistance from the tissues surrounding the tubule. [55]

The secreted frizzled-related proteins (SFRPs) antagonize WNT ligand protein binding to its receptor FZD. The double KO (dKO) of Sfrp1 and Sfrp2 genes results in a shortened WD and vas deferens. [56] Androgen administration to these animals never rescues this phenotype, indicating that the abnormalities in Sfrp1/2 dKO mutant male embryos are not caused by insufficient production of testosterone from the testes, but may reflect insensitivity of some target tissues to androgens. [56] It is also possible to consider that these phenotypes are, at least partially, a secondary consequence of the A-P extension defect of intermediate mesoderm formation described above. Although recent analyses have partially revealed the molecular mechanisms of ductal morphogenesis, further analyses should be performed including how androgen signaling regulates these molecules.

Postnatal differentiation: regional differentiation and epithelial cell differentiation

The epididymis consists of distinct anatomical regions that vary between species. However, in the mouse four regions can be defined: initial segment and caput, corpus and cauda epididymidis ([Figure 1]f). Each region is further divided into many segments characterized by expression of specific mRNAs, proteins and a repertoire of cell types. [57],[58] The segments, divided by septa, are observed after birth and are distinct during puberty, postnatal (P) days 14-35. Impaired epididymal regionalization or epithelial cell differentiation results in male infertility. For example, if the initial segment does not develop, then male infertility results. Data from efferent duct ligation (EDL) experiments suggested that luminal fluid coming from testis is responsible for the maintenance of initial segment cell survival, proliferation and differentiation. [59],[60]

Several growth factors, including FGFs 2,4 and 8, are detected in testicular fluid, and Fgfrs are expressed in the epithelium of the initial segment. [61],[62] During normal development, high activity of the MAPK pathway, especially p-MAPK1/3 (p-ERK1/2), is detected in the initial segment. [60] EDL abolishes their activities, emphasizing the importance of lumicrine factors regulating their activity. [60] Ros1 encodes an orphan receptor tyrosine kinase that is expressed in few epithelia, among them the WD and its derivatives. [63],[64],[65] Loss of Ros1 expression or a naturally-occurring mutation of Shp1 (me v), a negative regulator of ROS1, results in abnormal differentiation of the initial segment. [1],[66] RNase10-Cre drives gene recombination in the initial segment epithelia from P17 onward. RNase-Cre-mediated mutation in Pten, a negative regulator of PIP3/AKT signaling, induces dedifferentiation of the initial segment. [2] In these animals, abnormal differentiation results in an abnormally shaped initial segment. MAPK signaling regulators such as DUSP6 and FRS2 play important roles in epididymal cell proliferation and survival during postnatal development. [67],[68]

Androgens are important regulators of epididymal development from embryonic to adult stages. From later stages of development to the adult stage, Ar expression in the epithelia is greater than that in the mesenchyme. Several Ar KO mice have been reported, and the majority show a hypoplastic epididymis and defective epithelial cell differentiation. [47],[69],[70],[71] A differentiated epididymal epithelium is pseudostratified and comprises principal, clear, narrow, basal and recently-identified dendritic cells throughout the duct. [72],[73] Similar to other pseudostratified epithelia, for example the trachea, the epididymal luminal environment regulates secretion and absorption of ions, water, organic solutes and proteins. [74] The molecular mechanisms of epididymal epithelial differentiation are not clear. Chimeric mutation of the Ar indicates that defective epithelial cell differentiation is cell-autonomous. [47] Dicer and small RNAs also regulate epididymal development and epithelial cell differentiation partially through androgen action. [75],[76],[77]

Hox genes are evolutionarily-conserved transcriptional regulators that determine body patterning. [78] As found for body plan formation, vertebrae and the gut, Hox genes, Hoxa10 and Hoxa11 are suggested to determine the boundary between the epididymis and vas deferens. [79],[80],[81] Later studies by Snyder et al.[82] showed that there were additional region-specific (efferent ducts, epididymis and vas deferens) Hox transcripts that may define boundaries along the reproductive tract during development.

  Possible Contribution of Mouse Models to Understand Human Cinical Abnormalities Top

One of the most well-known congenital anomalies of the epididymis or vas deferens is congenital bilateral absence of the vas deferens (CBAVD). It occurs in 1%-2% of men with infertility. [83] 60%-90% of the CBAVD men harbor at least one associated cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation. [84] 10%-40% of CBAVD men do not have recognizable CFTR gene abnormalities accompanied by unilateral renal agenesis (URA). [85] Presumably, CBAVD patients have disrupted morphogenesis of the early mesonephros owing to the mutation of genes. [86] Those genes involved in mesonephros formation, e.g., Pax2, Wt-1 and Fgfs, may be viable candidate genes responsible for CBAVD with renal malformation.

Conversely, congenital anomalies of kidney and urinary tract (CAKUT) often carry mutations in genes, such as PAX2 and WT-1, and male mice carrying mutations of these genes also exhibit reproductive tract malformations. [87] Syndromes with renal tract abnormalities also carry mutations in the genes described above. Branchio-Oto-Renal (BOR) syndrome is a genetic condition that typically disrupts the development of tissues in the neck and causes malformations of the ears and kidneys. EYA1, the human homolog of the Drosophila eyes absent gene, is the most common gene responsible for BOR. [88] Further, Foxc1 regulates Eya1 expression. [28] Mutations in the SIX1 gene can be detected in 2% of individuals with the clinical diagnosis of BOR. [89] Mutations in both ROR2[90] and WNT5A[91] have been implicated in a rare genetic disease, Robinow syndrome, which exhibits several defects such as dwarfism, hydronephrosis and genital abnormalities. Because these syndromes often exhibit lethal abnormalities, it is still unclear if these mutations affect male fertility in humans.

Epididymal disjunction is the failure of the efferent ducts to reach the testis, which may reflect the failure of the efferent ducts to elongate, and presumably coil, during their development. [92],[93],[94],[95] Interestingly, one study [95] has shown that 30%-79% of boys with an undescended testis also have Wolffian duct abnormalities, of which 25% display epididymal disjunction. Therefore, it is important that epididymal abnormalities be detected at orchidopexy, or other male infertility, which may be classified as idiopathic, will result. As mentioned above, it is not clear how the efferent ducts form, elongate, are directed toward the testis and then fuse with the rete testis. Obviously, mouse models that display epididymal disjunction will greatly aid our understanding of this abnormality.

  Summary Top

One of the striking characteristics of the epididymis is its complex developmental process. The primordium of the epididymis, the mesonephros, arises as a part of the transient kidney, and its stability and differentiation are regulated by hormonal signaling including by androgens and growth factors. In human, it transforms its morphology to form a 6 m duct that is coiled and packed into a three-dimensional organ of approximately 10 cm in length. Recent studies utilizing a variety of transgenic mice have revealed the molecular contribution of numerous factors at each stage of epididymal development. The molecular dissection of the developmental mechanisms of the epididymis has just begun. Integrative understanding of the hierarchy and interaction of each factor will provide new directions in this field. Considering that the epididymis shares its origin with the urinary tract, it is noteworthy that the molecular mechanisms which lead to kidney mal-development, such as CAKUT, may provide significant insight for the mesonephros derivative mal-development, such as CBAVD and vice versa.

  Competing Financial Interests Top

Neither author declares a competing interest.

  Acknowledgments Top

We would like to thank Prof. Gen Yamada and Dr. Mika Okazawa for the supportive discussion. This work is supported by Grant-in-Aid for Young Scientists B (25860771), and National Institutes of Health Eunice Kennedy Shriver NICHD Grants HD069654 and HD068365 (BTH).[105]

  References Top

Sonnenberg-Riethmacher E, Walter B, Riethmacher D, Gödecke S, Birchmeier C. The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis. Genes Dev 1996; 10: 1184-93.  Back to cited text no. 1
Xu B, Washington AM, Hinton BT. PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility. Proc Natl Acad Sci U S A 2014; 111: 18643-8.  Back to cited text no. 2
Yeung CH, Cooper TG, Bergmann M, Schulze H. Organization of tubules in the human caput epididymidis and the ultrastructure of their epithelia. Am J Anat 1991; 191: 261-79.  Back to cited text no. 3
Atsuta Y, Tadokoro R, Saito D, Takahashi Y. Transgenesis of the Wolffian duct visualizes dynamic behavior of cells undergoing tubulogenesis in vivo. Dev Growth Differ 2013; 55: 579-90.  Back to cited text no. 4
Staack A, Donjacour AA, Brody J, Cunha GR, Carroll P. Mouse urogenital development: a practical approach. Differentiation 2003; 71: 402-13.  Back to cited text no. 5
Saxen, L. Organogenesis of the Kidney. Cambridge University Press; 1987.  Back to cited text no. 6
Torres M, Gómez-Pardo E, Dressler GR, Gruss P. Pax-2 controls multiple steps of urogenital development. Development 1995; 121: 4057-65.  Back to cited text no. 7
Bouchard M, Souabni A, Mandler M, Neubüser A, Busslinger M. Nephric lineage specification by Pax2 and Pax8. Genes Dev 2002; 16: 2958-70.  Back to cited text no. 8
Pedersen A, Skjong C, Shawlot W. Lim 1 is required for nephric duct extension and ureteric bud morphogenesis. Dev Biol 2005; 288: 571-81.  Back to cited text no. 9
Kobayashi A, Shawlot W, Kania A, Behringer RR. Requirement of Lim1 for female reproductive tract development. Development 2004; 131: 539-49.  Back to cited text no. 10
Miyamoto N, Yoshida M, Kuratani S, Matsuo I, Aizawa S. Defects of urogenital development in mice lacking Emx2. Development 1997; 124: 1653-64.  Back to cited text no. 11
Grote D, Souabni A, Busslinger M, Bouchard M. Pax2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney. Development 2006; 133: 53-61.  Back to cited text no. 12
Kitagaki J, Ueda Y, Chi X, Sharma N, Elder CM, et al. FGF8 is essential for formation of the ductal system in the male reproductive tract. Development 2011; 138: 5369-78.  Back to cited text no. 13
Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001;2(3):REVIEWS3005. Epub 2001 Mar 9. Review.  Back to cited text no. 14
Poladia DP, Kish K, Kutay B, Hains D, Kegg H, et al. Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme. Dev Biol 2006; 291: 325-39.  Back to cited text no. 15
Okazawa M, Murashima A, Harada M, Nakagata N, Noguchi M, et al. Region-specific regulation of cell proliferation by FGF receptor signaling during the Wolffian duct development. Dev Biol 2015; 400: 139-47.  Back to cited text no. 16
Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell 2005; 9: 283-92.  Back to cited text no. 17
Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, et al. Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 2009; 41: 793-9.  Back to cited text no. 18
de Martino C, Zamboni L. A morphologic study of the mesonephros of the human embryo. J Ultrastruct Res 1966; 16: 399-427.  Back to cited text no. 19
Tiedemann K, Egerer G. Vascularization and glomerular ultrastructure in the pig mesonephros. Cell Tissue Res 1984; 238: 165-75.  Back to cited text no. 20
Smith C, Mackay S. Morphological development and fate of the mouse mesonephros. J Anat 1991; 174: 171-84.  Back to cited text no. 21
Guttroff RF, Cooke PS, Hess RA. Blind-ending tubules and branching patterns of the rat ductuli efferentes. Anat Rec 1992; 232: 423-31.  Back to cited text no. 22
Ilio KY, Hess RA. Structure and function of the ductuli efferentes: a review. Microsc Res Tech 1994; 29: 432-67.  Back to cited text no. 23
Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 1998; 19: 87-90.  Back to cited text no. 24
Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, et al. WT-1 is required for early kidney development. Cell 1993; 74: 679-91.  Back to cited text no. 25
Sainio K, Hellstedt P, Kreidberg JA, Saxén L, Sariola H. Differential regulation of two sets of mesonephric tubules by WT-1. Development 1997; 124: 1293-9.  Back to cited text no. 26
Kobayashi H, Kawakami K, Asashima M, Nishinakamura R. Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech Dev 2007; 124: 290-303.  Back to cited text no. 27
Kume T, Deng K, Hogan BL. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 2000; 127: 1387-95.  Back to cited text no. 28
Murashima A, Akita H, Okazawa M, Kishigami S, Nakagata N, et al. Midline-derived Shh regulates mesonephric tubule formation through the paraxial mesoderm. Dev Biol 2014; 386: 216-26.  Back to cited text no. 29
Tong SY, Hutson JM, Watts LM. Does testosterone diffuse down the Wolffian duct during sexual differentiation? J Urol 1996; 155: 2057-9.  Back to cited text no. 30
Harding SD, Armit C, Armstrong J, Brennan J, Cheng Y, et al. The GUDMAP database - an online resource for genitourinary research. Development 2011; 138: 2845-53.  Back to cited text no. 31
McMahon AP, Aronow BJ, Davidson DR, Davies JA, Gaido KW, et al. GUDMAP: the genitourinary developmental molecular anatomy project. J Am Soc Nephrol 2008; 19: 667-71.  Back to cited text no. 32
Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, et al. A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway. Development 1997; 124: 2245-54.  Back to cited text no. 33
Lupien M, Diévart A, Morales CR, Hermo L, Calvo E, et al. Expression of constitutively active Notch1 in male genital tracts results in ectopic growth and blockage of efferent ducts, epididymal hyperplasia and sterility. Dev Biol 2006; 300: 497-511.  Back to cited text no. 34
Evrard YA, Lun Y, Aulehla A, Gan L, Johnson RL. Lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 1998; 394: 377-81.  Back to cited text no. 35
Hahn KL, Beres B, Rowton MJ, Skinner MK, Chang Y, et al. A deficiency of lunatic fringe is associated with cystic dilation of the rete testis. Reproduction 2009; 137: 79-93.  Back to cited text no. 36
Taguchi A, Kaku Y, Ohmori T, Sharmin S, Ogawa M, et al. Redefining the in vivo origin of metanephric nephron progenitors enables generation of complex kidney structures from pluripotent stem cells. Cell Stem Cell 2014; 14: 53-67.  Back to cited text no. 37
Yun K, Ajima R, Sharma N, Costantini F, Mackem S, et al. Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension. Hum Mol Genet 2014; 23: 6807-14.  Back to cited text no. 38
Jost A. Recherches sur la différenciation sexuelle de l'embryon de Lapin. Arch Anat Microsc Morphol Exp 1947; 36: 151-315.  Back to cited text no. 39
Lyon MF, Hawkes SG. X-linked gene for testicular feminization in the mouse. Nature 1970; 227: 1217-9.  Back to cited text no. 40
Matsumoto T, Takeyama K, Sato T, Kato S. Androgen receptor functions from reverse genetic models. J Steroid Biochem Mol Biol 2003; 85: 95-9.  Back to cited text no. 41
Welsh M, Sharpe RM, Walker M, Smith LB, Saunders PT. New insights into the role of androgens in Wolffian duct stabilization in male and female rodents. Endocrinology 2009; 150: 2472-80.  Back to cited text no. 42
Shima Y, Miyabayashi K, Haraguchi S, Arakawa T, Otake H, et al. Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testes. Mol Endocrinol 2013; 27: 63-73.  Back to cited text no. 43
DeFalco T, Capel B. Gonad morphogenesis in vertebrates: divergent means to a convergent end. Annu Rev Cell Dev Biol 2009; 25: 457-82.  Back to cited text no. 44
Jost A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog Horm Res 1953; 8: 379-418.  Back to cited text no. 45
Renfree MB, Fenelon J, Wijiyanti G, Wilson JD, Shaw G. Wolffian duct differentiation by physiological concentrations of androgen delivered systemically. Dev Biol 2009; 334: 429-36.  Back to cited text no. 46
Murashima A, Miyagawa S, Ogino Y, Nishida-Fukuda H, Araki K, et al. Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation. Endocrinology 2011; 152: 1640-51.  Back to cited text no. 47
Cunha GR, Young P, Higgins SJ, Cooke PS. Neonatal seminal vesicle mesenchyme induces a new morphological and functional phenotype in the epithelia of adult ureter and ductus deferens. Development 1991; 111: 145-58.  Back to cited text no. 48
Cunha GR, Alarid ET, Turner T, Donjacour AA, Boutin EL, et al. Normal and abnormal development of the male urogenital tract. Role of androgens, mesenchymal-epithelial interactions, and growth factors. J Androl 1992; 13: 465-75.  Back to cited text no. 49
Donjacour AA, Thomson AA, Cunha GR. FGF-10 plays an essential role in the growth of the fetal prostate. Dev Biol 2003; 261: 39-54.  Back to cited text no. 50
Gupta C. The role of epidermal growth factor receptor (EGFR) in male reproductive tract differentiation: stimulation of EGFR expression and inhibition of Wolffian duct differentiation with anti-EGFR antibody. Endocrinology 1996; 137: 905-10.  Back to cited text no. 51
Gupta C, Siegel S, Ellis D. The role of EGF in testosterone-induced reproductive tract differentiation. Dev Biol 1991; 146: 106-16.  Back to cited text no. 52
Tomaszewski J, Joseph A, Archambeault D, Yao HH. Essential roles of inhibin beta A in mouse epididymal coiling. Proc Natl Acad Sci U S A 2007; 104: 11322-7.  Back to cited text no. 53
Nie X, Arend LJ. Pkd1 is required for male reproductive tract development. Mech Dev 2013; 130: 567-76.  Back to cited text no. 54
Hirashima T. Pattern formation of an epithelial tubule by mechanical instability during epididymal development. Cell Rep 2014; 9: 866-73.  Back to cited text no. 55
Warr N, Siggers P, Bogani D, Brixey R, Pastorelli L, et al. Sfrp1 and Sfrp2 are required for normal male sexual development in mice. Dev Biol 2009; 326: 273-84.  Back to cited text no. 56
Johnston DS, Jelinsky SA, Bang HJ, DiCandeloro P, Wilson E, et al. The mouse epididymal transcriptome: transcriptional profiling of segmental gene expression in the epididymis. Biol Reprod 2005; 73: 404-13.  Back to cited text no. 57
Abou-Haïla A, Fain-Maurel MA. Regional differences of the proximal part of mouse epididymis: morphological and histochemical characterization. Anat Rec 1984; 209: 197-208.  Back to cited text no. 58
Turner TT, Riley TA. p53 independent, region-specific epithelial apoptosis is induced in the rat epididymis by deprivation of luminal factors. Mol Reprod Dev 1999; 53: 188-97.  Back to cited text no. 59
Xu B, Abdel-Fattah R, Yang L, Crenshaw SA, Black MB, et al. Testicular lumicrine factors regulate ERK, STAT, and NFKB pathways in the initial segment of the rat epididymis to prevent apoptosis. Biol Reprod 2011; 84: 1282-91.  Back to cited text no. 60
Lan ZJ, Labus JC, Hinton BT. Regulation of gamma-glutamyl transpeptidase catalytic activity and protein level in the initial segment of the rat epididymis by testicular factors: role of basic fibroblast growth factor. Biol Reprod 1998; 58: 197-206.  Back to cited text no. 61
Kirby JL, Yang L, Labus JC, Hinton BT. Characterization of fibroblast growth factor receptors expressed in principal cells in the initial segment of the rat epididymis. Biol Reprod 2003; 68: 2314-21.  Back to cited text no. 62
Sonnenberg E, Gödecke A, Walter B, Bladt F, Birchmeier C. Transient and locally restricted expression of the ros1 protooncogene during mouse development. EMBO J 1991; 10: 3693-702.  Back to cited text no. 63
Tessarollo L, Nagarajan L, Parada LF. c-ros: the vertebrate homolog of the sevenless tyrosine kinase receptor is tightly regulated during organogenesis in mouse embryonic development. Development 1992; 115: 11-20.  Back to cited text no. 64
Chen J, Zong CS, Wang LH. Tissue and epithelial cell-specific expression of chicken proto-oncogene c-ros in several organs suggests that it may play roles in their development and mature functions. Oncogene 1994; 9: 773-80.  Back to cited text no. 65
Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, et al. Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1. J Cell Biol 2001; 152: 325-34.  Back to cited text no. 66
Xu B, Yang L, Lye RJ, Hinton BT. p-MAPK1/3 and DUSP6 regulate epididymal cell proliferation and survival in a region-specific manner in mice. Biol Reprod 2010; 83: 807-17.  Back to cited text no. 67
Xu B, Yang L, Hinton BT. The role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of two activity levels of the components of the extracellular signal-regulated kinase (ERK) pathway in the mouse epididymis. Biol Reprod 2013; 89: 1-13.  Back to cited text no. 68
Simanainen U, McNamara K, Davey RA, Zajac JD, Handelsman DJ. Severe subfertility in mice with androgen receptor inactivation in sex accessory organs but not in testis. Endocrinology 2008; 149: 3330-8.  Back to cited text no. 69
Krutskikh A, De Gendt K, Sharp V, Verhoeven G, Poutanen M, et al. Targeted inactivation of the androgen receptor gene in murine proximal epididymis causes epithelial hypotrophy and obstructive azoospermia. Endocrinology 2011; 152: 689-96.  Back to cited text no. 70
O'Hara L, Welsh M, Saunders PT, Smith LB. Androgen receptor expression in the caput epididymal epithelium is essential for development of the initial segment and epididymal spermatozoa transit. Endocrinology 2011; 152: 718-29.  Back to cited text no. 71
Sun EL, Flickinger CJ. Development of cell types and of regional differences in the postnatal rat epididymis. Am J Anat 1979; 154: 27-55.  Back to cited text no. 72
Da Silva N, Cortez-Retamozo V, Reinecker HC, Wildgruber M, Hill E, et al. A dense network of dendritic cells populates the murine epididymis. Reproduction 2011; 141: 653-63.  Back to cited text no. 73
Shum WW, Da Silva N, McKee M, Smith PJ, Brown D, et al. Transepithelial projections from basal cells are luminal sensors in pseudostratified epithelia. Cell 2008; 135: 1108-17.  Back to cited text no. 74
Björkgren I, Saastamoinen L, Krutskikh A, Huhtaniemi I, Poutanen M, et al. Dicer1 ablation in the mouse epididymis causes dedifferentiation of the epithelium and imbalance in sex steroid signaling. PLoS One 2012; 7: e38457.  Back to cited text no. 75
Ma W, Xie S, Ni M, Huang X, Hu S, et al. MicroRNA-29a inhibited epididymal epithelial cell proliferation by targeting nuclear autoantigenic sperm protein (NASP). J Biol Chem 2012; 287: 10189-99.  Back to cited text no. 76
Ma W, Hu S, Yao G, Xie S, Ni M, et al. An androgen receptor-microrna-29a regulatory circuitry in mouse epididymis. J Biol Chem 2013; 288: 29369-81.  Back to cited text no. 77
McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell 1992; 68: 283-302.  Back to cited text no. 78
Hsieh-Li HM, Witte DP, Weinstein M, Branford W, Li H, et al. Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility. Development 1995; 121: 1373-85.  Back to cited text no. 79
Podlasek CA, Seo RM, Clemens JQ, Ma L, Maas RL, et al. Hoxa-10 deficient male mice exhibit abnormal development of the accessory sex organs. Dev Dyn 1999; 214: 1-12.  Back to cited text no. 80
Bomgardner D, Hinton BT, Turner TT. Hox transcription factors may play a role in regulating segmental function of the adult epididymis. J Androl 2001; 22: 527-31.  Back to cited text no. 81
Snyder EM, Small CL, Bomgardner D, Xu B, Evanoff R, et al. Gene expression in the efferent ducts, epididymis, and vas deferens during embryonic development of the mouse. Dev Dyn 2010; 239: 2479-91.  Back to cited text no. 82
Jequier AM, Ansell ID, Bullimore NJ. Congenital absence of the vasa deferentia presenting with infertility. J Androl 1985; 6: 15-9.  Back to cited text no. 83
Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, et al. Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA 1992; 267: 1794-7.  Back to cited text no. 84
Augarten A, Yahav Y, Kerem BS, Halle D, Laufer J, et al. Congenital bilateral absence of vas deferens in the absence of cystic fibrosis. Lancet 1994; 344: 1473-4.  Back to cited text no. 85
McCallum T, Milunsky J, Munarriz R, Carson R, Sadeghi-Nejad H, et al. Unilateral renal agenesis associated with congenital bilateral absence of the vas deferens: phenotypic findings and genetic considerations. Hum Reprod 2001; 16: 282-8.  Back to cited text no. 86
Pope JC 4 th , Brock JW 3 rd , Adams MC, Stephens FD, Ichikawa I. How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol 1999; 10: 2018-28.  Back to cited text no. 87
Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet 1997; 15: 157-64.  Back to cited text no. 88
Kochhar A, Orten DJ, Sorensen JL, Fischer SM, Cremers CW, et al. SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Hum Mutat 2008; 29: 565.  Back to cited text no. 89
Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, et al. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet 2000; 25: 419-22.  Back to cited text no. 90
Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, et al. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn 2010; 239: 327-37.  Back to cited text no. 91
Girgis SM, Etriby AN, Ibrahim AA, Kahil SA. Testicular biopsy in azoospermia. A review of the last ten years' experiences of over 800 cases. Fertil Steril 1969; 20: 467-77.  Back to cited text no. 92
Kroovand RL, Perlmutter AD. Congenital anomalies of the vas deferens and epididymis. In: SJ Hogan and ESE Hafez, editors. Pediatric Andrology. Boston: Martinus Nijhoff Publishers; 1981. p. 173-80.  Back to cited text no. 93
Turek PJ, Ewalt DH, Snyder HM, Duckett JW. Normal epididymal anatomy in boys. J Urol 1994; 151: 726-7.  Back to cited text no. 94
Zvizdic Z, Huskic J, Dizdarevic S, Karavdic K, Zvizdic D. Incidence of epididymal disjunction anomalies associated with an undescended testis. Folia Med 2009; 44: 65-8.  Back to cited text no. 95
Tzouanacou E, Wegener A, Wymeersch FJ, Wilson V, Nicolas JF. Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell 2009; 17: 365-76.  Back to cited text no. 96
Takemoto T, Uchikawa M, Yoshida M, Bell DM, Lovell-Badge R, et al. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 2011; 470: 394-8.  Back to cited text no. 97
Chia I, Grote D, Marcotte M, Batourina E, Mendelsohn C, et al. Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice. Development 2011; 138: 2089-97.  Back to cited text no. 98
Pole RJ, Qi BQ, Beasley SW. Patterns of apoptosis during degeneration of the pronephros and mesonephros. J Urol 2002; 167: 269-71.  Back to cited text no. 99
Wang Q, Lan Y, Cho ES, Maltby KM, Jiang R. Odd-skipped related 1 (Odd 1) is an essential regulator of heart and urogenital development. Dev Biol 2005; 288: 582-94.  Back to cited text no. 100
Mattiske D, Kume T, Hogan BL. The mouse forkhead gene Foxc1 is required for primordial germ cell migration and antral follicle development. Dev Biol 2006; 290: 447-58.  Back to cited text no. 101
Schuchardt A, D'Agati V, Pachnis V, Costantini F. Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development 1996; 122: 1919-29.  Back to cited text no. 102
Niederreither K, Subbarayan V, Dollé P, Chambon P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 1999; 21: 444-8.  Back to cited text no. 103
Hoshii T, Takeo T, Nakagata N, Takeya M, Araki K, et al. LGR4 regulates the postnatal development and integrity of male reproductive tracts in mice. Biol Reprod 2007; 76: 303-13.  Back to cited text no. 104
Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, et al. Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol 2006; 290: 421-34.  Back to cited text no. 105


  [Figure 1]

  [Table 1]

This article has been cited by
1 Mechanical Feedback Control for Multicellular Tissue Size Maintenance: A Minireview
Tsuyoshi Hirashima
Frontiers in Cell and Developmental Biology. 2022; 9
[Pubmed] | [DOI]
2 One Tool for Many Jobs: Divergent and Conserved Actions of Androgen Signaling in Male Internal Reproductive Tract and External Genitalia
Ciro M. Amato, Humphrey H-C. Yao, Fei Zhao
Frontiers in Endocrinology. 2022; 13
[Pubmed] | [DOI]
3 Crucial Convolution: Genetic and Molecular Mechanisms of Coiling during Epididymis Formation and Development in Embryogenesis
Joanne Wong, Jemma Gasperoni, Jarrad Fuller, Sylvia V. H. Grommen, Bert De Groef, Cathryn Hogarth, Sebastian Dworkin
Journal of Developmental Biology. 2022; 10(2): 25
[Pubmed] | [DOI]
4 Novel function of LHFPL2 in female and male distal reproductive tract development
Fei Zhao,Jun Zhou,Rong Li,Elizabeth A. Dudley,Xiaoqin Ye
Scientific Reports. 2016; 6(1)
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Development of W...
Possible Contrib...
Competing Financ...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded552    
    Comments [Add]    
    Cited by others 4    

Recommend this journal