doi: 10.1016/j.diff.2018.08.002. Epub 2018 Aug 23.
Human glans and preputial development
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- PMID:30245194
- PMCID: PMC6234068
- DOI: 10.1016/j.diff.2018.08.002
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Human glans and preputial development
Xin Liu et al. Differentiation.2018 Sep-Oct.
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Abstract
The urethra within the human penile shaft develops via (1) an "Opening Zipper" that facilitates distal canalization of the solid urethral plate to form a wide urethral groove and (2) a "Closing Zipper" that facilitates fusion of the epithelial surfaces of the urethral folds. Herein, we extend our knowledge by describing formation of the human urethra within the glans penis as well as development of the prepuce. Forty-eight normal human fetal penile specimens were examined using scanning electron microscopy and optical projection tomography. Serial histologic sections were evaluated for morphology and immunohistochemical localization for epithelial differentiation markers: Cytokeratins 6, 7, 10, FoxA1, uroplakin and the androgen receptor. As the closing zipper completes fusion of the urethral folds within the penile shaft to form a tubular urethra (~ 13 weeks), canalization of the urethral plate continues in proximal to distal fashion into the glans penis to directly form the urethra within the glans without forming an open urethral groove. Initially, the urethral plate is attached ventrally to the epidermis via an epithelial seam, which is remodeled and eliminated, thus establishing mesenchymal confluence ventral to the glanular urethra. The morphogenetic remodeling involves the strategic expression of cytokeratin 7, FoxA1 and uroplakin in endodermal epithelial cells as the tubular glanular urethra forms. The most ventral epithelial cells of the urethral plate are pinched off from the glanular urethra and are reabsorbed into the epidermis ultimately losing expression of their markers, a process undoubtedly regulated by androgens. The prepuce initially forms on the dorsal aspect of the glans at approximately 12 weeks of gestation. After sequential proximal to distal remodeling of the ventral urethral plate along the ventral aspect of glans, the prepuce of epidermal origin fuses in the ventral midline.
Keywords: Canalization; Development; Glans; Human; Penis; Prepuce; Urethra.
Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.
Figures
Scanning electron microscopic ontogeny of the developing human fetal penis and urethra from 10 to 16.5 weeks of gestation (A–E). Formation of the prepuce begins on the dorsal aspect of the glans penis (B), and after glandular urethral formation extends ventrally. In (B) note the prepuce dorso-laterally beginning to cover the glans. In (C–E) the preputial folds are approaching and fusing in the midline. The epithelial tag of unknown significance is present in A–C. Note also the curvature of the penile raphe in (E).
Scanning electron micrograph (G) and transverse sections of a 9-week human fetal penis stained with hematoxylin and eosin demonstrating (A) the solid urethral plate, (B) the beginning of canalization of the urethral plate, (C) the urethral plate has canalized to from an open urethral groove in the distal penile shaft, (D) mid-shaft showing a widely open urethral groove, (E) beginning of the process of fusion of the urethral folds, and (F) fully formed urethra at the levels indicated in (G). White arrowhead in (G) indicates the transition from penile shaft to glans. Modified from (Shen et al., 2016) with permission.
Sections through the human penile glans at 14 (A, C–E) and 15 weeks (B) gestation arranged in distal (A) to proximal (E) order. In (A) note the solid urethral plate located near the tip of the glans, which is surrounded by the preputial lamina. In (B) the urethral plate is canalizing at its junction with the epidermis. In (C) mesenchymal confluence (double-headed arrow) has been established ventral to the canalizing urethral plate whose dorsum is still solid. In (D) the canalization process is extending dorsally. In (E) a fully canalized urethra has developed. From (Liu et al., 2018a) with permission.
Mid-sagittal sections of the human fetal glandular urethra. (A) 14 weeks gestation, (B) 15 weeks, (C) 17 weeks and (D) 18 weeks. Note the progressive remodeling and formation of glandular urethra. The prepuce is present dorsally in each image with progressive ventral extension of the foreskin (C and D).
Immunochemical localization of cytokeratins 6, 7, 10 and FoxA1 in “mid” sagittal sections of the human glans penis at 14- and 17-weeks of gestation. Note at both the 14- and 17-week time points (A and D) cytokeratin 7 (red) localized to the terminal urethra and cytokeratin 6 to the skin and urethral plate (green). The endodermal marker FoxA1 (green) also localized to the terminal urethra (B, C, E and F) with K10 (red) localizing to the skin, and preputial lamina.
A single section of an 11-week human fetal penis immunostained for cytokeratin 6 and 10. In (A) note cytokeratin 6 (green) localized to the full epidermal thickness, the epithelial tag and the urethral plate. In (B) note cytokeratin 10 localized to supra-basal layers of the epidermis and the epithelial tag but not the urethral plate.
13-Week gestation human fetal penis with a representative low power histologic image through the glans, a macroscopic gross image, and corresponding serial sections in the distal, mid and proximal glans immunostained with androgen receptor (AR), cytokeratins 6, 7 and 10, FoxA1 and uroplakin. PPL = preputial lamina. Note the mesenchymal confluence ventral to the formed tubular urethra in the proximal glans (white asterisks) (proximal column M–R) and mesenchymal confluence in progress in the mid glans (white arrowheads) (middle column G–L). Note the open channels in the distal glans (white arrows) (distal column A–F) that will remodel into the urethra.
14-Week gestation human fetal penis with a representative low power histologic image through the glans, a macroscopic gross image, and corresponding serial sections in the distal, mid and proximal glans immunostained with androgen receptor (AR), cytokeratins 6, 7 and 10, FoxA1 and uroplakin. PPL = Preputial lamina. Note the completed mesenchymal confluence ventral to the formed tubular urethra in the proximal (M–R) and mid glans (G–L) (white asterisks). Note the open channels through which urine can pass in the distal glans (A–F) (white arrows). The endodermally derived epithelial cells that have pinched off, remodeled and ultimately resorbed are well visualized below the tubular urethra in the mid glans (G–L) (black arrows).
15-Week gestation human fetal penis with a representative low power histologic image through the glans, a macroscopic gross image, and corresponding serial sections in the distal, mid and proximal glans immunostained with androgen receptor (AR), cytokeratins 6, 7 and 10, FoxA1 and uroplakin. PPL=Preputial lamina. Note the tubular urethra in the proximal glans (M–R) with dorsal canalization still to occur (blue arrows). Mesenchymal confluence and pinched off, remodeled and ultimately resorbed epithelial cells (black arrows) are well visualized below the tubular urethra in the mid glans (G–L). Note the open channels in the distal glans (white arrows)(distal column A–F ) that will remodel into the urethra.
16-Week gestation human fetal penis with a representative low power histologic image through the glans, a macroscopic gross image, and corresponding serial sections in the distal, mid and proximal glans immunostained with androgen receptor (AR), cytokeratins 6, 7 and 10, FoxA1 and uroplakin. Note the formed tubular urethra in the mid (G–L) and proximal glans (M–R) (blue arrows) completed mesenchymal confluence and pinched off, remodeled and ultimately resorbed epithelial cells that are well visualized below the tubular urethra (black arrows). Note the AR positive cells at the site of the completed urethral formation (G and M) and in process mesenchymal confluence (A) (white asterisk). Note the open channels in the distal glans (white arrows) (distal column A–F) that will remodel into the urethra.
17-Week gestation human fetal penis with a representative low power histologic image through the glans, a macroscopic gross image, and corresponding serial sections in the distal, mid and proximal glans immunostained with Androgen Receptor (AR), cytokeratin 6, 7 and 10, FoxA1 and uroplakin. PPL=Preputial lamina. Note the formed tubular urethra in all the panels. The canalization process is now visible in the dorsal (light blue arrows) as well as the ventral aspect of the urethral and is at a more advanced stage in the proximal glans (M–R). Mesenchymal confluence and pinched off, remodeled and ultimately resorbed epithelial cells are well visualized below the tubular urethra in the mid glans (G–L) (black arrows) with the last remnants of reabsorbed cells still visible below the tubular urethra in the proximal glans (M–R) (black arrows). Mesenchymal confluence is not quite complete in the distal glans (A–F) (white asterisk).
Scanning electron microscopy, Ki67 Immunohistochemistry and optical projection tomography of 9 (A) and 10 (B) week human fetal penis. A and B: Note the progressive glandular tissue remodeling (green arrowhead) seen on the surface of the glans shown histologically in C (green arrowhead) and by optical projection tomography in D.
Optical Projection Ontogeny of the human fetal penis from 8–16 weeks gestation. The epithelial tag is seen from 9–12 weeks gestation (blue arrows). Note the progression of the urethral meatus from the penoscrotal junction to the tip of the penis (orange arrows). Extruded glandular canalization tissue can be seen from 11–14 weeks gestation (red arrows). Note the urethral plate in the 8 week specimen extending almost to the tip of glans (green arrow).
Near sagittal sections of human fetal penis at the ages indicated. At 9.5 weeks (A) the glans penis can be recognized, but there is no evidence of preputial development. Sections B–D are lateral to the midline. At 12.5 weeks the preputial lamina is seen dorsally (black arrow), but is absent ventrally (white arrow). At 14 (C) and 16 weeks (D) the preputial lamina is extensive dorsally (black arrows) and reduced in size ventrally (white arrows).
(A1–A3) are images of a 7.5-week human genital tubercle. A1 is a surface rendering generated by optical transmission tomography. Lines (A2) and (A3) indicate where the optical projection tomographic transverse sections were taken. At this stage there is no evidence of preputial development. (B) is a transverse section through the glans penis at 13 weeks immunostained for cytokeratin 6 (green) and cytokeratin 10 (red). Note the preputial placode (PP) dorsally between the white lines and the preputial laminae (PPL). (C) is a transverse section through the glans penis at 15 weeks. Note that the preputial lamina (PPL) has grown ventrally leaving a gap of mesenchyme destined to form the frenulum (white arrowhead). Ur = urethra.
Diagrammatic representation of human preputial development. Note the preputial placode in (A1 and A2). Separation of the preputial placode from the epidermis is seen in (B–D). Ventral expansion of the right and left preputial laminae is seen in (B–D). Note the ventral gap in the preputial lamina in (black arrowhead) (D2). Canalization of the urethral plate begins ventrally
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