Canalization of the urethral plate precedes fusion of the urethral folds during male penile urethral development: the double zipper hypothesis
Open accessAbstract
PURPOSE: We describe the "double zipper" mechanism of human male urethral formation, where the distal zipper opens the urethral groove through canalization of the urethral plate, and a second closing zipper follows behind and closes the urethral groove to form the tubular urethra. MATERIALS AND METHODS: Anonymous human fetal genital specimens were acquired and gender was determined by polymerase chain reaction of the Y chromosome. Specimens were processed for optical projection tomography, stained with E-cadherin, Ki67 and caspase 3, and imaged. RESULTS: Eight developing male fetal specimens from 6.5 to 16.5 weeks of gestation were analyzed by optical projection tomography, and an additional 5 specimens by serial sections. Phallus length ranged from 1.3 to 3.7 mm. The urethral plate canalized into a groove with 2 epithelial edges that subsequently fused. Ki67 staining was localized to the dorsal aspect of the urethral plate. In contrast, caspase 3 staining was not observed. The entire process was completed during a 10-week period. CONCLUSIONS: The human male urethra appears to form by 2 mechanisms, an initial "opening zipper" that facilitates distal canalization of the solid urethral plate to form the urethral groove, which involves a high rate of epithelial proliferation (apoptosis not observed), and a "closing zipper" facilitating fusion of the 2 epithelial surfaces of the urethral groove, and thus extending the penile urethra distally. Improved knowledge of the molecular mechanisms of these processes is critical to understanding mechanisms of abnormal urethral development, such as hypospadias.
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In humans, male-specific morphological differentiation of the genital tubercle/penis begins around 10 weeks of gestation, with closure of the urethral groove, and is complete by about gestation weeks 15-16.5.
“In humans, male-specific morphological differentiation of the genital tubercle/penis begins around 10 weeks of gestation (i.e., 8 weeks postconception), with closure of the urethral groove [6,7]. The process is complete by about gestation weeks 15–16.5 [6,7]”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [7]
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- Authors
- Li, Y., Sinclair, A., Cao, M., Shen, J., Choudhry, S., Botta, S., Cunha, G., & Baskin, L.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Baskin, Laurence
- Venue
- Journal of Urology
- Published
- 2015-04
- Volume
- 193
- Issue
- 4
- Pages
- 1353-1360
- ISSN
- 0022-5347 (ISSN-L)
- 1527-3792
- PMC
- PMC4456085
- OpenAlex
- W2141356284
- Cited by
- 97
- References
- 16
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 4 · 2020: 9 · 2019: 13 · 2018: 10 · 2017: 11 · 2016: 11 · 2015: 4
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Urology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-058105, K12DK083021, R01DK058105)
- Topics
- Health Sciences › Medicine › Urology › Urological Disorders and Treatments
- Health Sciences › Medicine › Surgery › Congenital Anomalies and Fetal Surgery
- Health Sciences › Medicine › Surgery › Genital Health and Disease
- Keywords
- penile urethra, epithelial cell proliferation, Ki-67, apoptosis, hypospadias, urethral malformation
- MeSH terms
- Gestational Age, Humans, Male, Morphogenesis, Penis, Urethra, Organogenesis
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