Tissue-specific roles of <i>Fgfr2</i> in development of the external genitalia

Gredler, Marissa L.; Seifert, Ashley W.; Cohn, Martin J.

doi:10.1242/dev.119891

Cited by 42 publications

(36 citation statements)

References 58 publications

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“…Fgf signaling also is important in genital development and sexual differentiation (40,(44)(45)(46). Our experiments revealed that Fgf9, Fgfr2, and Fgfr3 expression is diminished by prenatal exposure to flutamide, but Fgf9 and Fgfr2 show no response to neonatal exposure to estrogen.…”

Section: Discussionmentioning

confidence: 64%

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Zheng

Armfield

Cohn

2015

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

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105

129

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Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.sexual differentiation | external genitalia | congenital malformation | androgen | hypospadias

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Section: Discussionmentioning

confidence: 64%

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Zheng

Armfield

Cohn

2015

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

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105

129

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“…Urethral closure and differentiation of the phallus are under the regulation of complex gene networks. In mice, fibroblast growth factor 10 (FGF10) and its receptor fibroblast growth factor receptor 2 isoform IIIb (FGFR2IIIb) positively regulate genital tubercle (GT) outgrowth (Haraguchi et al 2000, Satoh et al 2004, Petiot et al 2005, Gredler et al 2015, Harada et al 2015. Deletion of Fgf10 or Fgfr2IIIb results in abnormal urethra formation (Haraguchi et al 2000, Satoh et al 2004, Petiot et al 2005, Gredler et al 2015, Harada et al 2015.…”

Section: Introductionmentioning

confidence: 99%

“…In mice, fibroblast growth factor 10 (FGF10) and its receptor fibroblast growth factor receptor 2 isoform IIIb (FGFR2IIIb) positively regulate genital tubercle (GT) outgrowth (Haraguchi et al 2000, Satoh et al 2004, Petiot et al 2005, Gredler et al 2015, Harada et al 2015. Deletion of Fgf10 or Fgfr2IIIb results in abnormal urethra formation (Haraguchi et al 2000, Satoh et al 2004, Petiot et al 2005, Gredler et al 2015, Harada et al 2015. FGF10, acting via the FGFR2IIIb receptor (Ornitz et al 1996, Zhang et al 2006, may direct epithelium-mesenchymal crosstalk and regulate GT patterning and urethral closure (Satoh et al 2004, Gredler et al 2015, Harada et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

Chen

Pask

et al. 2019

Reproduction

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The development of the mammalian phallus involves hormone-dependent mesenchymal-epithelial signalling mechanisms that contribute to urethral closure and regulation of phallus elongation and growth. In marsupials, most differentiation and growth of the phallus occurs post-natally, making them amenable to direct hormone treatment. Expression of IGFs, FGFs, EFNB2, MAFB, DLX5 and AP-1 mRNAs in the phallus at day 50 post-partum (pp) were altered after treatment of tammar wallaby young from day 20 to 40 pp with androgen, oestrogen or after castration at day 25 pp. However, the most interesting changes occurred in the IGF pathway genes. Androgen treatment upregulated IGF1 in female phalluses and oestrogen treatment upregulated IGF1 in male phalluses, but it was downregulated by castration. IGFBP3 was higher in female phalluses and downregulated by androgen. IGF1 expression was higher in all untreated male than in female phalluses from day 50 to 150 pp, but IGFBP3 had the reverse pattern. At day 90 pp, when urethral closure in males is progressing and male phallus growth is accelerating. IGF1 and PCNA protein were only detected in the male urorectal septum, suggesting for the first time that closure and elongation may involve IGF1 activation of cell proliferation specifically in male phalluses. These effects of sex steroids on gene expression and on the IGF1 signalling pathway in particular, suggest that the developing phallus may be especially susceptible to perturbation by exogenous hormones.Reproduction (2019) 157 1-12

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“…The significance of the ectoderm has been clearly shown in an elegant study from Cohn’s group demonstrating that the contact between ectodermal and endodermal epithelia, i.e., the formation of the cloacal membrane, is crucial for GT initiation (Seifert et al, 2009b). The ectoderm’s importance in signaling regulation is also demonstrated by the fact that GT malformations are observed in ectoderm-specific Fgfr2 (Gredler et al, 2015) and Smoothened (Seifert et al, 2009a) conditional knockout animals. The authors of these papers also noted that the ventral ectoderm, along with the underlying cloacal epithelium, might also play a structural role possibly regulated by HH or FGF signaling.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic mechanisms involved in this early androgen-independent phase of genital development are not yet fully understood. Nonetheless, investigations using knockout mouse models have demonstrated that the canonical Wnt (Lin et al, 2008; Miyagawa et al, 2009), Fgf (Gredler et al, 2015; Haraguchi et al, 2000; Lin et al, 2013; Petiot et al, 2005; Seifert et al, 2009b), Bmp (Suzuki et al, 2003) and Shh (Haraguchi et al, 2001; Lin et al, 2009; Miyagawa et al, 2009; Perriton et al, 2002; Seifert et al, 2009a; Seifert et al, 2010) signaling pathways are involved in the initiation and continuous development of the GT. Before e14.5 (Suzuki et al, 2002) GT development is identical in both sexes.…”

Section: Introductionmentioning

confidence: 99%

Requirement for basement membrane laminin α5 during urethral and external genital development

Lin

Werner²,

et al. 2016

Mechanisms of Development

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Hypospadias, a congenital malformation of the penis characteristic of an abnormal urethral orifice, affects 1 in every 125 boys, and its incidence is rising. Herein we test the hypothesis that the basement membrane protein laminin α5 (LAMA5) plays a key role in the development of the mouse genital tubercle, the embryonic anlage of the external genitalia. Using standard histological analyses and electron microscopy, we characterized the morphology of the external genitalia in Lama5 knockout (LAMA5-KO) mouse embryos during both androgen-independent genital tubercle development and androgen-mediated sexual differentiation. We compared regulatory gene expression between control and LAMA5-KO by in situ hybridization. We also examined the epithelial structure of the mutant genital tubercle using immunofluorescence staining and histological analyses of semi-thin sections. We found that Lama5 was expressed in both ectodermal and endodermal epithelia of the cloaca. The LAMA5-KO displayed a profound external genital malformation in which the genital tubercle was underdeveloped with a large ectopic orifice at the proximal end. In older embryos, the urethra failed to form a tubular structure and was left completely exposed. These defects were not associated with a significant alteration in regulatory gene expression, but rather with a defective ectodermal epithelium and an abnormal disintegration of the cloacal membrane. We conclude that LAMA5 is required in the basement membrane to maintain normal architecture of the ventral ectoderm during genital tubercle development, which is essential for the formation of a tubular urethra. Perturbation of LAMA5, and possibly other basement membrane components, may cause hypospadias in humans.

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Tissue-specific roles of Fgfr2 in development of the external genitalia

Cited by 42 publications

References 58 publications

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

Requirement for basement membrane laminin α5 during urethral and external genital development

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