Review article
Hypospadias and anorectal malformations mediated by defective Eph/ephrin signaling,☆☆

https://doi.org/10.1016/j.jpurol.2007.01.199Get rights and content

Abstract

Purpose

Despite extensive research, the molecular basis of hypospadias and anorectal malformations is poorly understood, likely due to a multifactorial basis. The incidence of hypospadias is increasing, thus making research in this area warranted and timely. This review presents recent molecular work broadening our understanding of these disorders.

Materials and methods

A brief review of our recent work and the literature on the role of Eph/ephrin signaling in hypospadias and anorectal malformations is presented.

Results

Genetically engineered mice mutant for ephrin-B2 or EphB2;EphB3 manifest a variety of genitourinary and anorectal malformations. Approximately 40% of adult male ephrin-B2lacZ/+ heterozygous mice demonstrate perineal hypospadias. Although homozygous mice die soon after birth, 100% of homozygous males demonstrate high imperforate anus with urethral anomalies and 100% of homozygous females demonstrate persistent cloaca. Male mice compound homozygous null for EphB2;EphB3 also demonstrate hypospadias.

Conclusions

These mouse models provide compelling evidence of the role of B-class Eph/ephrin signaling in genitourinary/anorectal development and add to our mechanistic and molecular understanding of normal and abnormal embryonic development. As research on these molecules continues, they will likely be shown to contribute to the multifactorial basis of hypospadias and anorectal malformations in humans as well.

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.

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  • Cited by (0)

    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).

    ☆☆

    Selcuk Yucel is supported by Akdeniz University Scientific Research and Project Unit.

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