Review articleHypospadias and anorectal malformations mediated by defective Eph/ephrin signaling☆,☆☆
Section snippets
Hypospadias
Hypospadias is the second most common human birth defect, affecting 1 in 125 male births [1]. Despite the high incidence, our current understanding of the etiology of hypospadias is at best incomplete. It is well understood that the androgen signaling cascade, including testosterone (T) regulation, production and biosynthesis, the peripheral conversion of T by 5-alpha-reductase to dihydrotestosterone (DHT), and T/DHT–androgen receptor interactions [2], [3] mediate virilization of the genital
Anorectal malformations
Congenital anorectal malformations are common surgical problems affecting 1 in 1500 to 1 in 5000 live births, with an even gender distribution [11], [12], [13], [14]. In humans, they present as a spectrum of abnormalities ranging from an ectopic anus, to an imperforate anus with fistula to the distal genitourinary tract, to complex cloacal abnormalities. To date, six genetic mouse models of anorectal malformations exist, namely Sonic hedgehog (Shh) [15], [16], [17], [18], Gli2 and Gli3[18], [19]
Embryology
To fully understand hypospadias, anorectal malformations and how they might be linked, a review of normal embryology is warranted. In Fig. 2, the process by which the cloaca (Latin – “sewer”) is septated is depicted, yielding separation of the urinary and fecal streams during normal embryonic development. Classic teaching describes the cloacal septation event occurring by the ingrowth of epithelium-covered mesenchymal folds, termed the cranial to caudal Tourneaux fold and the lateral to medial
Endocrine disruptor theory and hypospadias
It is well established that humans continually ingest substances with known estrogenic activity, such as insecticides utilized in crop production, natural plant estrogens, by-products of plastic production and pharmaceuticals. In fact, the canned food industry uses some chemical substances with estrogenic activity to cover the inner surface of cans. All endocrine disruptors find their way into fresh or seawater to be accumulated in higher organisms at the top of food chain. Therefore, top
B-class Eph/ephrin mutant mouse model
Our research group is investigating a novel genetically engineered murine model manifesting the unanticipated phenotype of hypospadias and genitourinary/anorectal malformations. The Eph and ephrin gene families (Fig. 4) are known for their roles in cell–cell signaling, cell sorting [32], axonal guidance during neuronal development [33], [34], delineation of embryonic cellular boundaries [35], vasculogenesis [36], [37] and epithelial–mesenchymal transitions [38]. The Eph receptors, the largest
Organ culture system
In order to address whether EphB2 might be an androgen-regulated gene, an organ culture system was used wherein embryonic genital tubercles from the EphB2 heterozygous mice (EphB2lacZ/+) could be grown. In these mice with normal genitalia, EphB2 expression is highlighted by the beta-galactosidase color reaction (blue). Embryonic day 12.5 (E12.5) genital tubercles from females and males were microdissected and grown in culture for 2 days with and without the presence of DHT. As seen in Fig. 11,
Conclusions
The B-class Eph/ephrin cell–cell signaling pathway is crucial in mouse urethral and anorectal development and EphB2 is a candidate androgen-regulated gene. Many studies are currently underway further exploring the mouse model and the role these molecules may play in human hypospadias and urogenital/anorectal development.
References (43)
- et al.
Genital malformations and coexistent urinary tract or spinal anomalies in patients with imperforate anus
J Urol
(1997) - et al.
Anorectal malformations caused by defects in sonic hedgehog signaling
Am J Pathol
(2001) - et al.
The development of the male genitourinary system. I. The origin of the urorectal septum and the formation of the perineum
Br J Plast Surg
(2004) - et al.
Urethral development in the fetal rabbit and induction of hypospadias: a model for human development
J Urol
(2000) - et al.
Control of cell behaviour by signalling through Eph receptors and ephrins
Curr Opin Neurobiol
(2000) - et al.
Ephrin-As as receptors and ephrins in neural development
Nat Rev Neurosci
(2002) - et al.
Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4
Cell
(1998) - et al.
Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells
Dev Biol
(2001) - et al.
Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development
Dev Biol
(2004) - et al.
Dihydrotestesterone induction of EPHB2 expression in the female genital tubercle mimics male pattern of expression during embryogenesis
J Urol
(2003)
Fibroblast growth factor 10 (Fgf10) invalidation results in anorectal malformation in mice
J Ped Surg
Ephrins in reverse, park and drive
Trends Cell Biol
Hypospadias trends in two US surveillance systems
Pediatrics
The endocrine control of male phenotypic development
Aust J Biol Sci
Steroid 5 alpha-reductase 2 deficiency
Endocr Rev
Lack of defects in androgen production in children with hypospadias
J Clin Endocrinol Metab
International trends in rates of hypospadias and cryptorchidism
Environ Health Perspect
The ‘oestrogen hypothesis’ – where do we stand now?
Int J Androl
Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome
Reproduction
Urological implications of imperforate anus
AUA Update Series
The genetics of anorectal malformations: a complex matter
Semin Pediatr Surg
Cited by (0)
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This work was funded in part by NIH R01 DK 59164 (Baker, PI), NIH R01 DK 59164-S1 (Baker, PI – Garcia, Mentoree) and a Children's Medical Center at Dallas Clinical Research Grant (Garcia, PI).
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Selcuk Yucel is supported by Akdeniz University Scientific Research and Project Unit.