Development of the mammalian urethra is controlled by Fgfr2-IIIb

Petiot, Anita; Perriton, Claire L.; Dickson, Clive; Cohn, Martin J.

doi:10.1242/dev.01778

Cited by 105 publications

(172 citation statements)

References 52 publications

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“…Although the incidence of hypospadias is increasing, its etiology remains unknown. Several genes are suggested as the candidate genes for the urethral formation based on analyses of knockout mice (10,(29)(30)(31)(32)(33) that Mafb is a pivotal mediator of androgen actions during embryonic urethral masculinization. Another characteristic of the masculinization of external genitalia is the difference in the GT organ size.…”

Section: Discussionmentioning

confidence: 99%

“…Another characteristic of the masculinization of external genitalia is the difference in the GT organ size. Regulation of cell proliferation by growth factors has been suggested as an essential process for the GT development (30,(34)(35)(36). Genedriven GT outgrowth regulated by several growth factors has been proposed as essential for androgen-independent early embryonic GT growth.…”

Section: Discussionmentioning

confidence: 99%

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Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Suzuki

Numata

Suzuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.Mafb | masculinization | urethra | hypospadias | androgen receptor

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Suzuki

Numata

Suzuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The FGF gene family, especially FGF10 [26], is also implicated in the development of external genitalia in mice [27]. In humans, polymorphisms of FGF8, FGF10 and FGFR2 may be associated with an increased risk of hypospadias [28].…”

Section: Is Related To Mutations Of Homeoboxa13 (Hoxa13) Hoxa13 Allomentioning

confidence: 99%

Hypospadias: Interactions between environment and genetics

Kalfa

Philibert

Baskin

et al. 2011

Molecular and Cellular Endocrinology

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“…Fgf10À/À deficient mutant male mice, as well as mice lacking the IIIb isoform of Fgfr2, exhibit a phenotype consistent with hypospadias, with normal corporal bodies, but disturbed urethral plate ventral fusion. 13,14 In these mice, urethral signaling regions are established, but cell proliferation is prematurely arrested and maturation of the urethral epithelium is disrupted. Interestingly, these genes are downstream targets of AR during external genital development, as the loss of Fgfr2-IIIb and Fgf10 expression in the urethra, and associated hypospadias phenotype, is observed as an effect of AR antagonists.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, these genes are downstream targets of AR during external genital development, as the loss of Fgfr2-IIIb and Fgf10 expression in the urethra, and associated hypospadias phenotype, is observed as an effect of AR antagonists. 14 These observations prompted us to screen the FGFR2, FGF10, FGF8, and BMP7 and genes in boys with hypospadias.…”

Section: Introductionmentioning

confidence: 99%

FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias

et al. 2007

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Hypospadias is a common malformation, which results from failure of urethral tube closure, and whose molecular mechanisms are still largely unknown. The normal genital development is orchestrated by the urethral plate epithelium (UPE), at the genital tubercle (GT), which has polarizing activity, controlling a network of epithelial-mesenchymal interactions, which, when disturbed, may lead to hypospadias. Homeobox proteins (HOXs), fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) are essential in this process. Hypospadias in the Hoxa13 À/À mice occurs as a result of the combined loss of Fgf8 and Bmp7 expression in the UPE. In both Fgf10 and Fgfr2 deficient mutant hypospadic male mice, cell proliferation is arrested prematurely and the maturation of the urethral epithelium is disrupted. Fgf8, Fgf10, and their receptor Fgfr2 are downstream targets of androgens (AR) during external genital development, an important fact given the pivotal role of AR in male sex differentiation. Therefore, we examined FGFR2, FGF10, FGF8, and BMP7 as candidate genes for hypospadias. DNA from 60 boys with familial, isolated, hypospadias was screened for mutations in FGFR2, FGF10, FGF8, and BMP7 genes, using DHPLC and DNA sequence analysis. The sequence variations c. and, c.550 þ 27C4T, c.727 þ 180T4G, c.830T4C (p.Me186Thr), and c.2454C4T in FGFR2 were found uniquely in patients with hypospadias, as compared with 96 controls. No genetic variant in the other genes was detected. These results indicate that mutations are rare in FGF8 and FGFR2 in hypospadias, but gene variants may influence the risk.

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Development of the mammalian urethra is controlled by Fgfr2-IIIb

Abstract: SummaryDevelopment of the mammalian urethra is controlled by Fgfr2-IIIb

Cited by 105 publications

References 52 publications

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Hypospadias: Interactions between environment and genetics

FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias

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