Functional and phylogenetic analysis shows that<i>Fgf8</i>is a marker of genital induction in mammals but is not required for external genital development

Seifert, Ashley W.; Yamaguchi, Terry P.; Cohn, Martin J.

doi:10.1242/dev.036830

Cited by 57 publications

(68 citation statements)

References 44 publications

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“…Our preliminary analyses of conditional Fgfr mutants reveal GT defects (our unpublished results), and Fgfr1-null mutants have caudal agenesis (Deng et al, 1994;Yamaguchi et al, 1994). Dispensable Fgf8 function was also recently demonstrated (Seifert et al, 2009).…”

Section: ;Ctnnb1mentioning

confidence: 56%

Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

et al. 2009

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Embryonic appendicular structures, such as the limb buds and the developing external genitalia, are suitable models with which to analyze the reciprocal interactions of growth factors in the regulation of outgrowth. Although several studies have evaluated the individual functions of different growth factors in appendicular growth, the coordinated function and integration of input from multiple signaling cascades is poorly understood. We demonstrate that a novel signaling cascade governs formation of the embryonic external genitalia [genital tubercle (GT)]. We show that the dosage of Shh signal is tightly associated with subsequent levels of Wnt/-catenin activity and the extent of external genitalia outgrowth. In Shh-null mouse embryos, both expression of Wnt ligands and Wnt/-catenin signaling activity are downregulated. -catenin gain-of-function mutation rescues defective GT outgrowth and Fgf8 expression in Shh-null embryos. These data indicate that Wnt/-catenin signaling in the distal urethral epithelium acts downstream of Shh signaling during GT outgrowth. The current data also suggest that Wnt/-catenin regulates Fgf8 expression via Lef/Tcf binding sites in a 3Ј conserved enhancer. Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among multiple Fgfs in GT development. Our results provide new insights into the integration of growth factor signaling in the appendicular developmental programs that regulate external genitalia development.

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Section: ;Ctnnb1mentioning

confidence: 56%

Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

et al. 2009

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“…Urethral epithelium is endoderm in origin. This UE signaling center relies on a series of morphogenetic signaling molecules, such as Shh (18,26,27), Hoxa13 and Hoxd13 (28), BMP7 (17), Fgfs (17,29,30), and receptor Fgfr2 (11). These molecules are expressed in the UE and play a critical role in various morphogenetic events.…”

Section: Discussionmentioning

confidence: 99%

Fkbp52 Regulates Androgen Receptor Transactivation Activity and Male Urethra Morphogenesis

Chen

Yong

Hinds

et al. 2010

Journal of Biological Chemistry

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Hypospadias is a common birth defect in humans, yet its etiology and pattern of onset are largely unknown. Recent studies have shown that male mice with targeted ablation of FK506-binding protein-52 (Fkbp52) develop hypospadias, most likely due to actions of Fkbp52 as a molecular co-chaperone of the androgen receptor (AR). Here, we further dissect the developmental and molecular mechanisms that underlie hypospadias in Fkbp52-deficient mice. Scanning electron microscopy revealed a defect in the elevation of prepucial swelling that led to the onset of the ventral penile cleft. Interestingly, expression of Fkbp52 was highest in the ventral aspect of the developing penis that undergoes fusion of the urethral epithelium. Although in situ hybridization and immunohistochemical analyses suggested that Fkbp52 mutants had a normal urethral epithelium signaling center and epithelial differentiation, a reduced apoptotic cell index at ventral epithelial cells at the site of fusion and a defect of genital mesenchymal cell migration were observed. Supplementation of gestating females with excess testosterone partially rescued the hypospadic phenotype in Fkbp52 mutant males, showing that loss of Fkbp52 desensitizes AR to hormonal activation. Direct measurement of AR activity was performed in mouse embryonic fibroblast cells treated with dihydrotestosterone or synthetic agonist R1881. Reduced AR activity at genes controlling sexual dimorphism and cell growth was found in Fkbp52-deficient mouse embryonic fibroblast cells. However, chromatin immunoprecipitation analysis revealed normal occupancy of AR at gene promoters, suggesting that Fkbp52 exerts downstream effects on the transactivation function of AR. Taken together, our data show Fkbp52 to be an important molecular regulator in the androgen-mediated pathway of urethra morphogenesis.Male external genital development in mammals is composed of distinct hormone-independent and hormone-dependent stages (1-3). The first phase (androgen-independent) is characterized by initial patterning and outgrowth of genitourinary structures in both male and female early embryos (embryonic day (E)10.5-E13.5 in the mouse). In males, the second phase (androgen-dependent) involves further outgrowth and differentiation of the glans penis, closure of the urethral fold (urethral epithelium remodeling) and scrotal development. Insufficient or altered hormonal signaling during development leads to many birth defects in the reproductive system, including hypospadias (4, 5). Hypospadias is a common birth defect in humans, in which altered urethral epithelial fusion causes ectopic openings at the ventral surface of the male external tubercle. Hypospadias is thought to result from androgen insufficiency or insensitivity. However, most cases of hypospadias have no clear link to defects in androgen production or androgen receptor (AR) 3 mutations (5). Fkbp52 and Fkbp51 are the best known of several tetratricopeptide repeat proteins that co-chaperone steroid receptors, including AR, progesterone receptor, and...

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“…This confirms that FGF8 still serves as a significant indicator of protrusion and sustained outgrowth of GT. Furthermore, it appears that the expression of FGF8 dictates whether GT protrusion occurs in the Wnt5a mutants [Suzuki et al, 2003;Seifert et al, 2009]. The regulation of FGF8 has been suggested to also depend on SHH signaling.…”

Section: Development Of the Bipotential External Genitaliamentioning

confidence: 99%

Development of the External Genitalia and Their Sexual Dimorphic Regulation in Mice

Ipulan¹,

Suzuki²,

Matsushita³

et al. 2014

Sex Dev

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The study of the external genitalia is divided into 2 developmental stages: the formation and growth of a bipotential genital tubercle (GT) and the sexual differentiation of the male and female GT. The sexually dimorphic processes, which occur during the second part of GT differentiation, are suggested to be governed by androgen signaling and more recently crosstalk with other signaling factors. The process of elucidating the regulatory mechanisms of hormone signaling towards other signaling networks in the GT is still in its early stages. Nevertheless, it is becoming a productive area of research. This review summarizes various studies on the development of the murine GT and the defining characteristics of a masculinized GT and presents the different signaling pathways possibly involved during masculinization.

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Functional and phylogenetic analysis shows thatFgf8is a marker of genital induction in mammals but is not required for external genital development

Cited by 57 publications

References 44 publications

Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program

Fkbp52 Regulates Androgen Receptor Transactivation Activity and Male Urethra Morphogenesis

Development of the External Genitalia and Their Sexual Dimorphic Regulation in Mice

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