Neuroanatomical ontogeny of the human fetal penis

Baskin, Laurence S.; Lee, Y.T.; Cunha, Gerald R.

doi:10.1046/j.1464-410x.1997.00119.x

Cited by 64 publications

(26 citation statements)

References 9 publications

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“…The stromal tissue surrounding the urethral epithelium shows a relatively weak density of AR expression genital specimens from normal human males of gestational ages 12-20 weeks were utilized. Based on past experience, the age of the fetal specimens, and previous experience with fetal and postnatal hypospadias, we made the assumption that the specimens analyzed represented normal development (Baskin et al 1997(Baskin et al , 1998(Baskin et al , 2001Baskin 2000). The specimens were subdivided into two gestational age groups, 12-14 weeks and 16-20 weeks.…”

Section: Preparation Of the Human Tissuesmentioning

confidence: 99%

Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra

et al. 2001

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Normal penile development is dependent on testosterone, its conversion via steroid 5 alpha-reductase type 2 to dihydrotestosterone, and a functional androgen receptor (AR). The goal of this study was to investigate the distribution of AR and 5 alpha-reductase type 2 in the developing human fetal external genitalia with special emphasis on urethra formation. Twenty fetal genital specimens from normal human males (12-20 weeks gestation) were sectioned serially and stained by avidin-biotinylated peroxidase complex method with antigen retrieval. Stained sections throughout male genital development documented the expression of AR and 5 alpha-reductase type 2 in the phallus. Between 12 and 14 weeks of gestation, AR was localized to epithelial cells of the urethral plate in the glans, the tubular urethra of the penile shaft, and stromal tissue surrounding the urethral epithelium. In the fetal penis between 16 and 20 weeks gestation, the density of AR expression was greatest in urethral epithelial cells versus the surrounding stromal tissues. There was a characteristic pattern of AR expression in the glandular urethral epithelium between 16 and 20 weeks gestation. AR expression was greater along the ventral aspect of the glandular urethra than along the dorsal aspect of the urethral epithelium. The expression of 5 alpha-reductase type 2 was localized to the stroma surrounding the urethra, especially along the urethral seam area in the ventral portion of the remodeling urethra. These anatomical studies support the hypothesis that androgens are essential for the formation of the ventral portion of the urethra and that abnormalities in either the AR or 5 alpha-reductase type 2 can explain the occurrence of hypospadias.

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Section: Preparation Of the Human Tissuesmentioning

confidence: 99%

Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra

et al. 2001

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“…Transverse sections (6 µm thick) were cut on a microtome. Serial sections were (1) stained to detect apoptosis by using the terminal transferase nuclear end labeling (TUNEL) method, (2) immunostained with antibodies to E-cadherin, cytokeratin 8, smooth muscle α-actin, and vimentin, or (3) stained with hematoxylin and eosin (Baskin et al 1997). Briefly, the avidin-biotin-peroxidase procedure was employed by using Vectastatin ABC kits (Vector laboratories, Burlingame, Calif.) with cobalt intensification.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic defects in the androgen metabolism pathway, e.g., 5α-II reductase defects or androgen receptor defects, are known to result in hypospadias (Wilson et al 1993;Griffin et al 1995). These specific defects in androgen metabolism, however, do not explain the etiology of the overwhelming majority of hypospadias cases, specifically moderate and mild forms of hypospadias (Allen and Griffin 1984;Allera et al 1995;Sutherland et al 1996;Albers et al 1997;Silver and Russell 1999) During development of the penile urethra in humans, the urethral folds fuse and make contact in the midline to form an epithelial seam (Baskin et al 1997;Kurzrock et al 1999a) Subsequently, the epithelial seam disappears resulting in the normal tubular urethra. Abnormalities in urethral seam formation and remodeling may explain hypospadias.…”

Section: Introductionmentioning

confidence: 99%

Urethral seam formation and hypospadias

Baskin

Erol

Jegatheesan

et al. 2001

Cell and Tissue Research

124

101

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Knowledge of the formation of the normal male urethra may elucidate the etiology of hypospadias. We describe urethral formation in the mouse, show the similarities and relevance to human urethral development, and introduce the concept of the epithelial seam formation and remodeling during urethral formation. Three mechanisms may account for epithelial seam formation: (1) epithelial-mesenchymal transformation similar to that described in the fusion of the palatal shelves, (2) apoptosis, and/or (3) tissue remodeling via cellular migration. Urethral development in the embryonic mouse (14-21 days of gestation) was compared with urethral formation in embryonic human specimens (8-16 weeks of gestation) by using histology, immunohistochemistry, and three-dimensional reconstruction. The urethra forms by fusion of the epithelial edges of the urethral folds, giving a midline epithelial seam. The epithelial seam is remodeled via cellular migration into a centrally located urethra and ventrally displaced remnant of epithelial cells. The epithelial seam is remodeled by narrowing approximately at its midpoint, with subsequent epithelial migration into the urethra or penile skin. The epithelial cells are replaced by mesenchymal cells. This remodeling seam displays a narrow band (approximately 30 microns wide) of apoptotic activity corresponding to the mesenchymal cells and not to epithelial cells. No evidence was seen of the co-expression of cytokeratin and mesenchymal markers (actin or vimentin). Urethral seam formation occurs in both the mouse and the human. Our data in the mouse support the hypothesis that seam transformation occurs via cellular migration and not by epithelial mesenchymal transformation or epithelial apoptosis. We postulate that disruption of epithelial fusion remodeling, and cellular migration leads to hypospadias.

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“…Gender of the embryos was confirmed using polymerase chain reaction for the SRY gene. On EDs 15,16,18,and 19, the GT of male embryos was harvested.…”

Section: Animalsmentioning

confidence: 99%

“…Urethral plate fusion generates the urethral seam (16,17), and hence disorder of urethral seam fusion is a plausible mechanism that may lead to hypospadias (18,19). Others have proposed that epithelialmesenchymal transformation (EMT), epithelial apoptosis, and epithelial cell migration are the key processes involved in the urethral seam formation.…”

mentioning

confidence: 99%

Epithelial–mesenchymal transformation and apoptosis in rat urethra development

et al. 2017

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BACKGROUND:To examine the mechanism of urethral seam formation during embryonal development of rat urethra. METHODS: Time-mated Sprague-Dawley rats were killed and the genital tubercles of male pups harvested on embryonic day (ED) 15, 16, 18, and 19. External morphology was observed under scanning electron microscope. Serial transverse sections were prepared to examine dynamic changes in the urethral seam morphology with hematoxylin-eosin staining, immunohistochemistry, transmission electron microscopy, and double immunofluorescence. RESULTS: Bilateral outgrowth of urethral swelling followed by urethral plate fusion in the midline to form urethral seam was observed from ED 16 onwards. Coexpression of epithelial and mesenchymal markers was observed in several cells at the urethral seam; a few cells with coexpression of epithelial and apoptotic markers were also observed. Mesenchymal transformation of epithelial cells and apoptotic epithelial cells was observed under transmission electron microscope. CONCLUSION: Urethral formation occurs by tubulogenesis, which initiates proximally and progresses distally. This is the first study to demonstrate epithelial-mesenchymal transformation and epithelial cell apoptosis in the urethral seam cells of fetal rats. These findings provide new insights into the mechanisms involved in embryonal development of the urethra.

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Neuroanatomical ontogeny of the human fetal penis

Cited by 64 publications

References 9 publications

Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra

Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra

Urethral seam formation and hypospadias

Epithelial–mesenchymal transformation and apoptosis in rat urethra development

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