The British Association of Plastic Surgeons (2004) 57, 112–121

The development of the male genitourinary system: II. The origin and formation of the urethral plate

P.J. Hynes*, J.P. Fraher

Department of Anatomy, University College Cork, Cork, Ireland

Received 10 May 2002; accepted 21 August 2003

KEYWORDS Summary The origin, extent and topographical relationships of the urethral plate and Urethral plate; its role in the pathogenesis of developmental anomalies (bladder extrophy, epispadias Epispadias; Hypospadias; and hypospadias) remain incompletely resolved. The commonly held view that the ; Urethra urethral plate (the forerunner of the urethra) arises through distal proliferation of the cells of the anterior wall of the cloaca cannot explain these anomalies. Given this and its newfound implications for hypospadias repair the development of the urethral plate is presented in detail. New insights into the origin of associated congenital defects are revealed. Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved.

The origin of the urethral plate and its role in another view considers that the urethral plate development of the urethra has been the subject of results from apposition of the walls of the divergent views. According to most investigators cloaca.13 – 15 Moreover, the relationship of the the of the anterior cloacal wall prolifer- urethral plate and the cloacal membrane and ates and forms the epithelial urethral plate, which their roles in the pathogenesis of developmental grows anteriorly in the of the genital anomalies is poorly understood.10,12,16,17 Some tubercle. It remains in contact with the believe that bladder extrophy and epispadias result covering the caudal median surface of the tubercle from excessive lengthening of the cloacal mem- 3,9,20 at the cloacal groove.1–8 The urethral plate is brane early in development. Whilst hypospa- considered to be the precursor of the glandar dias is considered by most to result from failure of 2,5,6,9,16,17,21 urethra only, the remainder of the penile urethra fusion of the urethral folds, van der 3 developing from the itself. Others Putte postulates that it results from a defect in the propose that the urethral plate is the precursor of cloacal membrane. the whole penile urethra.9,10 According to another This study entails a re-assessment of normal hypothesis the ectoderm lining the cloacal groove development and aims to resolve these inconsis- proliferates to form the urethral plate and the tencies. A clear understanding of the origin and latter is therefore ectodermal in origin.11,12 Yet topography of the urethral plate is important because of its new-found implications for hypospa- 24,25 *Corresponding author. dias repair. The use of native urethral epi- E-mail address: [email protected] thelium in hypospadias repair in an attempt to

S0007-1226/$ - see front matter Q 2004 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2003.08.018 The development of the male genitourinary system: II. The origin and formation of the urethral plate 113 simulate normal urethral form requires a detailed rostral mesoderm of ; up, urethral knowledge of this epithelium and its extent. plate; urs, ; us, urogenital sinus.

Materials and method Observations

Details of the material used, including fixation, The cloaca and the formation of the genital embedding, sectioning, staining, image capture and tubercle processing, have been given previously.22 The same sets of serial sections were used to examine the At embryonic day 11 (E11) the membranous cloaca formation of the urethral plate. (mc) is separated from the amniotic cavity (ac) by Computer assisted three-dimensional recon- the cloacal membrane (cm) (Fig. 1(a)). As the latter structions were made from sections at 30 mm is traced rostrally the superficial dense mesoderm intervals, using a Kontron image analysis system. of the cloacal folds (cf) extends progressively As before (paper I), the final reconstruction was further medially between its two epithelial com- sectioned virtually so as to view the median sagittal ponents, the cloacal endoderm and surface ecto- structures from a right lateral perspective. The derm (Fig. 1(b) and (c)). With this, the width of the resulting images were stored in a Harvard Graphics cloacal membrane decreases correspondingly. As it programme. The dimensions of individual struc- does so, its depth increases progressively, due to an tures were measured directly from the calibrated increase in the number of its endodermal cell reconstructions (Fig. 9). layers. This mesodermal extension continues to increase Abbreviations used in text: ac, amniotic cavity; ap, in degree during E11, particularly rostrally and apical part of glans; c, corona; cd, cloacal duct; cf, caudally. Thus, the depth of the endodermal cloacal fold; cg, cloacal groove; cm, cloacal component of the cloacal membrane (cm) con- membrane; gt, genital tubercle; hg, ; mc, tinues to increase whilst its breadth decreases (Fig. membranous cloaca; pc, phallic cloaca; pug, 2(a)–(c)). During this period also, the rostral cloaca primitive urethral groove; rc, rostral cloaca; rmgt, (rc) is becoming partitioned into the hindgut (hg)

Fig. 1 (a) Reconstructed mid-sagittal section of an E11 specimen. (b) and (c) Light micrographs of transverse sections of an E11 specimen. Their levels are indicated in (a). As the membranous cloaca (mc) is traced rostrally the superficial mesoderm of the cloacal folds (cf) comes closer to the midline. With this the depth of the cloacal membrane increases. Key to labels in Figs. 1–8: ac, amniotic cavity. ap, apical part of glans. c, corona. cd, cloacal duct. cf, cloacal fold. cg, cloacal groove. cm, cloacal membrane. cs, coronal sulcus. dw, dorsal body wall. hg, hindgut. ic, . iuw, infra-umbilical ventral wall. mc, membranous cloaca. md, . pc, phallic cloaca. pf, preputial fold. pug, primitive urethral groove. rc, rostral cloaca. rmgt, rostral mesoderm of genital tubercle. t, tail. tg, tail gut. ud, urogenital duct. up, urethral plate. urs, urorectal septum. us, urogenital sinus. Arrowheads indicate apoptosis. Note: in Figs. 1(a)–6(a), red, yellow and grey represent ectoderm, endoderm and mesoderm, respectively. 114 P.J. Hynes, J.P. Fraher

Fig. 2 (a) Reconstructed mid-sagittal section of a late E11 specimen. (b) and (c) Light micrographs of transverse sections of a late E11 specimen. Their levels are indicated in (a). The depth of the cloacal membrane (cm) continues to increase. Key to labels are given in caption of Fig. 1.

Fig. 3 (a) Reconstructed mid-sagittal section of an E12 specimen. The rostral end of the now deep cloacal membrane (cm) is being displaced towards the tip of the GT by the RMGT. (b) and (c) Light micrographs of transverse sections of an E12 specimen. Their levels are indicated in (a). Key to labels are given in caption of Fig. 1. The development of the male genitourinary system: II. The origin and formation of the urethral plate 115 and the urogenital sinus (us) by the urorectal Formation of the urethral plate septum (urs) (Fig. 2(a)). As a result of continued growth of the rostral Initially, early in E12 the phallic cloaca (pc) extends mesoderm of the genital tubercle (rmgt) (Figs. from the caudal to the rostral surfaces of the 3(a) and 4(a)) during E12, by E13 it has genital tubercle (gt). Its membrane is continuous overgrown the cloacal fold mesoderm distally with the ectoderm of the cloacal groove (cg), which to form the tip of the genital tubercle (gt) and extends onto its distal, rostral surface (Fig. 3(a) and the apical part of the glans (ap) (Fig. 5(a)). With (b)). As the rmgt extends distally, it progressively this the membranous cloaca (mc) and the cuts off this continuity with the rostral surface (Fig. cloacal folds no longer reach the tip of the gt. 4(a)–(d)). As a result, by E13 it fails to reach quite Most of the membranous cloaca extends distally to the tip of the gt as the rmgt overgrows it to form in the caudal median region of the gt as the the apical part of the glans (ap) (Fig. 5(a) and (b)). phallic cloaca (pc) (Figs. 3(a) and (c), and 4(a) Over the same period the cloacal folds (cf) come and (c)). The rmgt forms the deep wall of the closer to the median plane and the cloacal latter, the cloacal folds (cf) form its lateral membrane (cm) continues to become deeper and walls, and its ventral and caudal walls are narrower (Fig. 3(a) and (b)). By late E12, the distal formed by the ventral part of the cloacal walls of the phallic cloaca (pc) come together to membrane (cm) (Fig. 4). The proximal part of comprise a solid, sagittally orientated, median the membranous cloaca, which lies superficial to plate of endoderm, the urethral plate (up) (Fig. the urorectal septum (urs), forms the cloacal 4(a) and (b)). This remains in continuity with the duct (cd) (Fig. 4(a)). ectoderm at the bottom of the cloacal groove (cg)

Fig. 4 (a) Reconstructed mid-sagittal section of a late E12. The sidewalls of the distal part of the phallic cloaca are coming into apposition and the urethral plate (up) is beginning to form. (b)–(e) Light micrographs of transverse sections of late E12. Their levels are indicated in (a). A small median cyst-like cavity persists, separate from that of the phallic cloaca (a) and (c). Key to labels are given in caption of Fig. 1. 116 P.J. Hynes, J.P. Fraher

Fig. 5 (a) Reconstructed mid-sagittal section of an E13 specimen. The corona (c) is evident and the RMGT has extended distal to the urethral plate (up) to form the apical part of the glans (ap). The urethral plate now reaches proximally as far as the base of the glans. (b)–(f) Light micrographs of transverse sections of an E13 specimen. Their levels are indicated in (a). Key to labels are given in caption of Fig. 1.

(Fig. 4(b)–(d)). Its median plane remains evident are reciprocal to the appearance of the adjacent where the apices of its constituent cells are mesoderm of the rmgt rostrally and of the cloacal apposed to one another. Few if any cells extend folds (cf) laterally. As it tapers, its epithelial walls across the midline. Also, a small median cyst-like thicken proximodistally. This is particularly the space remains evident within it (Fig. 4(c)). Its case with regard to its roof epithelium where thickness is uniform distally but more proximally its adjacent cloacal fold indentation is more pro- profile on transverse section is that of a narrow nounced throughout (Figs. 5(d)–(f), 6(c)–(e), and inverted triangle (Fig. 4(b)–(d)). 7(c) and (d)). The phallic cloaca (pc) tapers distally through- With the progressive apposition of the walls of out. The taper is progressively more pronounced the phallic cloaca (pc) the urethral plate (up) from stage to stage (Figs. 4(a), 5(a), 6(a), 7(a) and continues to extend proximally (Fig.3(a)and 8). With this, its walls come together at progress- 4(a)). At E13 its proximal end is at the base of the ively more proximal levels where they are continu- glandar part of the GT. By this stage the latter is ous with the solid urethral plate (up) (Figs. 5(c) and distinct from the shaft with the development of the (d), 6(b) and (c), and 7(b) and (c)). Thus, the shape corona (c) (Fig. 5). Its length increases (Fig. 9) and of the cloaca on cross-section varies from level to it is at mid-shaft level by E15 (Figs. 6(a), 7(a) and 8). level and from stage to stage. Initially, its proximal Moreover, the absolute length of the phallic cloaca part is circular or oblong (Fig. 4(e)) but comes to be decreases, while that of the urethral plate triangular (Fig. 5(f)) and then indented with a increases in a reciprocal manner (Fig. 9). Also, stellate profile by E14 (Fig. 6(e)). The indentations relative to that of the GT, the length of the phallic The development of the male genitourinary system: II. The origin and formation of the urethral plate 117

Fig. 6 (a) Reconstructed mid-sagittal section of E14. (b)–(e) Light micrographs of sections of E14. Their levels are indicated in (a). Key to labels are given in caption of Fig. 1. cloaca decreases somewhat whilst that of the ventral part of the cloacal membrane more proxi- urethral plate increases. Subsequent to E15 the mally (Fig. 6(b) and (c)). phallic cloaca comes to extend through the urethral plate with a consequent decrease in length and regression of the latter (Fig. 9). Discussion Distal to the phallic cloaca (pc), the epithelium of the urethral plate (up) shows similar reciproca- The membranous cloaca extends to the base of the tion in form, relative to the mesoderm. On section body stalk (umbilicus) at E1122 (paper 1). It comes it tends to be triangular proximally and flattened to be displaced from here with the development of from side to side distally. In this direction too, it the genital tubercle (GT) and its wall extends to the becomes progressively less indented by the rmgt rostral surface of the latter for a period. With and by the deep mesoderm of the cloacal folds (cf) further growth of the rostral mesoderm of the (Figs. 5(b)–(d), 6(b) and (d), and 7(b) and (c)). genital tubercle (RMGT) the membranous cloaca Throughout, the median plane is evident where the (now renamed the phallic cloaca) is displaced into apices of its constituent cells are apposed to one the caudal part of the GT. It comes to lie on the another. They are strictly orientated at right angles caudal aspect of the shaft and the proximal two to the locus of the lumen and very few of them thirds of the glans. At the same time, its endoder- encroach on this. mal lining apposes distally and this apposition By E14 the dorsal part of the cloacal membrane progresses proximally. Its walls are apposed in the (cm) has disintegrated (Fig. 6(a)). Consequently, proximal glans and distal shaft where it forms the the dorsal part of the cloacal groove has disap- urethral plate. The phallic cloaca is the precursor of peared. Its remaining ventral part is termed the the shaft urethra and the proximal two thirds of the primitive urethral groove (pug). This is the surface glandar urethra. indication of the urethral plate (up) distally and the Both the depth and the width of the cloacal 118 P.J. Hynes, J.P. Fraher

Fig. 7 (a) Reconstructed mid-sagittal section of a late E14 specimen. The urethral plate (up) has extended further proximally into the distal part of the shaft. Its part formed by the cloacal membrane (cm) is separated from that formed by the phallic cloaca by a dotted line. With development of the preputial fold (pf) the coronal sulcus (cs) becomes distinct. (b)–(d) Light micrographs of transverse sections of a late E14 specimen. Their levels are indicated in (a). Key to labels are given in caption of Fig. 1. membrane vary along its length, one being inversely brane is shallow and broad. This reciprocal associ- proportional to the other. The extent to which the ation may be explained on the basis of compression associated mesoderm approaches the midline also of the cloacal epithelium by mesodermal growth. varies. A close approach is associated with a By extension, many of the developmental changes narrow, deep membrane. By contrast, when the in the epithelia of the GT, including the linings of mesoderm is further from the midline the mem- the cloaca and its derivatives, may also be inter- preted as resulting from compression by the associated mesoderm. The likelihood that this association represents a causal relationship is

Fig. 8 Reconstructed mid-sagittal section of E15. The urethral plate has reached mid-shaft level. Key to labels are given in caption of Fig. 1. Fig. 9 The development of the male genitourinary system: II. The origin and formation of the urethral plate 119 strengthened by a close examination of the changes sponding reciprocal symmetry in the adjacent in the form and dimensions of the cloaca and also of mesodermal growth patterns. the appearances of the epithelia. Thus, as the The origin, extent and topographical relation- mesoderm approaches the midline more closely, ships of the urethral plate remain incompletely the lumen of the membranous cloaca decreases in resolved. It is commonly described as arising depth and comes to lie progressively further through distal proliferation of the cells of the cephalad in the GT. Progressive apposition of the anterior wall of the phallic cloaca.2–10 Descriptions lateral cloacal epithelial walls in a cephalad show reciprocal variations in the extent of the direction can account for both of these changes. phallic cloaca and the urethral plate. The urethral Similarly, epithelial apposition in the phallic plate is described as extending along the entire 13 – 15 cloaca takes place as a result of compression of length of the shaft in sheep and opossum. In 16 its lateral and dorsal walls, by the deep mesoderm the rat, Kluth found no evidence of a urethral of the cloacal folds and by the RMGT, respectively. plate and described the phallic cloaca as extending These processes can readily account for the highly as far as the tip of the genital tubercle whilst 12 regular and bilaterally symmetrical transverse Forsberg considered the urethral plate to be sectional profiles of the urethral plate epithelium. confined to the glans. Descriptions in man have 10 The superficial part of this plate lies in the median varied: Glenister described the urethral plate as sagittal plane, while its deep part is either extending along the entire length of the genital tubercle (except for the distal one third of the transverse or biconcave relative to the coronal 17 plane of the GT. The latter profile is compatible glans) but Altemus and Hutchins considered it to be confined to the glans. In the pig, it extends as far with compression on its deep aspect by the RMGT. 4 In this instance, the urethral plate as a whole is as the proximal part of the genital tubercle. In cruciform on transverse section. The presence of marsupials at birth, the urethral plate extends to the tip of the genital tubercle and reaches the median cystic spaces in the deep part of the rostral surface of the glans.14,15 This indicates that urethral plate is also compatible with such a the RMGT fails to reach the tip of the glans in process; these may come to be formed as remnants marsupials, an arrangement resembling that of the of the cloacal cavity isolated following mesodermal early stage of the mammalian genital tubercle. compression. As a result of the above processes of These inconsistencies could represent real fusion the epithelia of the phallic cloaca come to developmental differences between species or comprise the deep part of the urethral plate. The may have arisen because different developmental remainder of this is formed by the ventral (distal) stages were examined. They are more readily part of the cloacal membrane (Fig. 7). This fusion of interpreted on the basis of the mechanism of epithelia continues disto-proximally into the distal mesodermal compression proposed in the current part of the shaft (E15). The decrease in the absolute hypothesis than by variations in urethral plate and relative lengths of the phallic cloaca and the epithelial proliferation. The current hypothesis reciprocal increase in the absolute and relative can explain them on the basis of variation in a lengths of the urethral plate are consistent with the single factor, namely, the extent to which the proposed hypothesis. epithelial walls of the phallic cloaca come together The arrangement of the cells of the various parts (under mesodermal pressure). This process may of the urethral plate is also compatible with the cease at different levels in different species. above hypothesis. Those formerly comprising Moreover, the predominant use of sagittal sec- the roof of the phallic cloaca lie transversely in tions by most other investigators is likely to have the coronal plane of the GT. These are apposed to given rise to difficulties of interpretation of urethral one another in the plane of the obliterated lumen. plate morphology. The entire length of this narrow The erstwhile lumen is also evident in the median median structure is unlikely to be incorporated on sagittal plane of the superficial part of the urethral any single sagittal section. Accurate reconstruc- plate. In each location, the cells are strictly tions or measurements of the dimensions of its orientated at right angles to the locus of the epithelial sheets, or of the cloaca would therefore lumen and very few of them encroach on this. be difficult to achieve. The current study therefore Thus, they retain aspects of their former organis- has the additional crucial advantage that transverse ation. As they are traced to the phallic cloaca their sections enable clear demonstration of the consist- orientation changes little if at all as the lumen ency and extent of the loci of the median planes of appears. The transition is smooth. Moreover, the apposition of epithelial layers, a central feature of remarkable symmetry of the profiles of the urethral the proposed hypothesis of epithelial apposition. plate and phallic cloaca is matched by a corre- Complete or partial failure of the proposed 120 P.J. Hynes, J.P. Fraher processes of mesodermal proliferation and conse- from this level and progressively from the rostral quent epithelial compression may explain several of and distal aspects of the genital tubercle. the congenital abnormalities found in this region. A † Complete or partial failure of RMGT proliferation number may arise from variations in the encroach- will result in failure of this displacement and in ment by the RMGT on the membranous cloaca. bladder extrophy and variable degrees of epis- Initially, the latter extends to the base of the body padias, respectively. stalk. With the growth of RMGT, its rostral end is † The cloacal membrane and the membranous displaced from this level and progressively from the cloaca (renamed the phallic cloaca) come to lie rostral and distal aspect of the genital tubercle, so on the caudal aspect of the shaft and the that it finally lies on the caudal aspect of the proximal two thirds of the glans. developing glans. At the same time, the endoder- † Progressive disto-proximal apposition of the mal linings of its left and right walls become walls of the phallic cloaca results in the apposed to one another progressively from this formation of a solid plate of endodermal epi- end, forming the urethral plate. Complete failure of thelium, the urethral plate. This process may this process of mesodermal proliferation will result become arrested at different levels in different in failure of this displacement. This, combined with species. cloacal membrane rupture will result in bladder † The phallic cloaca and the urethral plate are the extrophy and epispadias. Partial failure will result precursors of the urethra of the penile shaft and in varying degrees of epispadias alone. Epispadias the proximal two thirds of the glandar urethra. combined with incomplete fusion of the urethral † Hypospadias arises later in development if fusion folds on the undersurface of the developing phallus of the urethral folds becomes arrested or a will result in cleft glans penis.18,19 The commonly discontinuity in the urethral plate epithelium held view that the origin of the urethral plate (the pre-empts such fusion. forerunner of the urethra) results from epithelial proliferation through the caudal aspect of the genital tubercle cannot explain these anomalies. Development of the marsupial genital tubercle is Acknowledgements arrested at an earlier stage in its development than in the mouse (see above). This arrangement The authors wish to thank Mrs B. Riedewald, Mrs foreshadows the later appearance of bifurcation A. Marsh and Mr D. O’ Leary of the Department of of the glans in the marsupial. Hypospadias, on the Anatomy, University College, Cork, for the techni- other hand, may arise later in development if fusion cal assistance provided and the Health Research of the urethral folds becomes arrested or a Board of Ireland, for its financial support. discontinuity in the urethral plate/cloacal epi- thelium (due to a continuity of cloacal fold mesoderm across the midline) pre-empts such References fusion.23 Thus, one fundamental process, namely, meso- 1. Vaughan ED, Middleton GW. Pertinent genitourinary embry- dermal growth leading to epithelial compression ology: review for practicing urologist. Urology 1975;6: and fusion, can explain a whole series of complex 139—49. events in the development of the lower urinary 2. Williams DI. The development and abnormalities of the penile urethra. Acta Anat 1952;15:176—85. tract in the male. The hypothesis gains considerable 3 Van der Putte SCJ. 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