title: Canalization of the urethral plate precedes fusion of the urethral folds during male penile urethral development: the double zipper hypothesis.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Adriane
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Mei
authors.initials: M
authors.lastname: Cao
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Joel
authors.initials: J
authors.lastname: Shen
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Shweta
authors.initials: S
authors.lastname: Choudhry
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Sisir
authors.initials: S
authors.lastname: Botta
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California.
authors.forename: Gerald
authors.initials: G
authors.lastname: Cunha
authors.affiliation: Division of Pediatric Urology, Benioff Children's Hospital, UCSF, San Francisco, California. Electronic address: lbaskin@urology.ucsf.edu.
authors.forename: Laurence
authors.initials: L
authors.lastname: Baskin
mesh_terms: D005865:Gestational Age; D006801:Humans; D008297:Male; D009024:Morphogenesis; D038081:Organogenesis; D010413:Penis / Q000196:embryology*; D014521:Urethra / Q000196:embryology*
keywords: growth and development; hypospadias; organogenesis; urethra