Tissue‐specific roles of FGF signaling in external genitalia development

Harada, Mikio; Omori, Akiko; Nakahara, Chiaki; Nakagata, Naomi; Akita, Keiichi; Yamada, Gen

doi:10.1002/dvdy.24277

Cited by 35 publications

(32 citation statements)

References 72 publications

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“…MAFB expression was higher in female phalluses at day 50 pp than that in male phalluses, upregulated after castration in males, but not affected by androgen treatment nor oestrogen treatment. FGF10, FGFR2IIIb, EFNB2, MAFB and DLX5 were all expressed in the urethral epithelium as well as in the phallus epithelium in the tammar, as shown in mice (Haraguchi et al 2001, Perriton et al 2002, Dravis et al 2004, Petiot et al 2005, Gredler et al 2015, Harada et al 2015. In mice, these genes are all crucial for maintaining cell proliferation and cell survival in the phallus (Bhushan et al 2001, Shaulian & Karin 2001, Bendall et al 2003, Hart et al 2003, Steinberg et al 2005, Weiler et al 2009, Yu et al 2016.…”

Section: Figurementioning

confidence: 88%

“…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%

“…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. EphrinB2 (EFNB2) is expressed in the ventral midline of the GT and cooperates with its receptor, tyrosine-protein kinase receptor EPH-3 (EPHB2) through a directional signalling pathway to maintain normal urorectal development in mice (Adams 2002, Dravis et al 2004, Yucel et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Figurementioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

Chen

Pask

et al. 2019

Reproduction

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“…Congenital malformations of the penis are among the most common human birth defects, with hypospadias — an incomplete formation of the urethral tube that is characterized by ectopic, multiple or oversized urethral meatus — affecting approximately 1 in 250 live male births 1 . Although the causes of hypospadias remain poorly understood, progress in mouse developmental genetics has identified a small number of genes with essential roles in urethral tubulogenesis 2–7 . Nonetheless, the details of the gene regulatory networks involved in genital development remain largely uncharacterized 3,8 .…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of the Genital Organizer: Gene Expression Profile of the Mouse Urethral Plate Epithelium

et al. 2016

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Purpose Lower urinary tract malformations are among the most common congenital anomalies in humans. Molecular genetic studies of mouse external genital development have begun to identify mechanisms that pattern the genital tubercle and orchestrate urethral tubulogenesis. The urethral plate epithelium is an endodermal signaling region that plays an essential role in external genital development; however, little is known about the molecular identity of this cell population or the genes that regulate its activity. Material and Methods We used microarray analysis to characterize differences in gene expression between urethral plate epithelium and surrounding tissue in mouse genital tubercles. In situ hybridizations were performed to map gene expression patterns and ToppCluster was used to analyze gene associations. Results Here we report on 84 genes enriched at least 20-fold in urethral plate epithelium relative to surrounding tissue. We show that the majority of these genes are expressed throughout the urethral plate in males and females at E12.5, when the urethral plate is known to signal. Functional analysis using ToppCluster revealed genetic pathways with known functions in other organ systems but unknown roles in external genital development. Additionally, a 3D molecular atlas of genes enriched in urethral plate epithelium has been generated and deposited at the GenitoUrinary Development Molecular Anatomy Project website (GUDMAP.org). Conclusions This study identifies dozens of genes previously unknown to be expressed in the urethral plate epithelium at a crucial developmental period, and provides a novel panel of genes for analysis in animal models and in humans with external genital anomalies.

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Spatiotemporal map of key signaling factors during early penis development

Tarulli

Cripps

Pask

et al. 2021

Developmental Dynamics

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The formation of the external genitalia is a highly complex developmental process, considering it involves a wide range of cell types and results in sexually dimorphic outcomes. Development is controlled by several secreted signalling factors produced in complex spatiotemporal patterns, including the hedgehog (HH), bone morphogenic protein (BMP), fibroblast growth factor (FGF) and WNT signalling families. Many of these factors act on or are influenced by the actions of the androgen receptor (AR) that is critical to masculinisation. This complexity of expression makes it difficult to conceptualise patterns of potential importance. Mapping expression during key stages of development is needed to develop a comprehensive model of how different cell types interact in formation of external genitalia, and the global regulatory networks at play. This is particularly true in light of the sensitivity of this process to environmental disruption during key stages of development. The goal of this review is to integrate all recent studies on gene expression in early penis development to create a comprehensive spatiotemporal map. This serves as a resource to aid in visualising potentially significant interactions involved in external genital development.

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Tissue‐specific roles of FGF signaling in external genitalia development

Cited by 35 publications

References 72 publications

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

Effects of androgen and oestrogen on IGF pathways controlling phallus growth

Molecular Characterization of the Genital Organizer: Gene Expression Profile of the Mouse Urethral Plate Epithelium

Spatiotemporal map of key signaling factors during early penis development

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