Regulatory roles of epithelial-mesenchymal interaction (EMI) during early and androgen dependent external genitalia development

Hyuga, Taiju; Suzuki, Kentaro; Acebedo, Alvin R.; Hashimoto, Daiki; Kajimoto, Mizuki; Miyagawa, Shinichi; Enmi, Jun Ichiro; Yoshioka, Yoshichika; Yamada, Gen

doi:10.1016/j.diff.2019.08.004

Cited by 13 publications

(14 citation statements)

References 75 publications

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“…Several hypotheses are proposed to explain the mechanism of urethral closure. One of the hypotheses is that the proliferation of cells in urorectal septum (URS) contributes to the urethral closure [73][74][75]. Interestingly, IGF1 is localized in the mesenchyme of the URS only in male phalluses at day 90 pp, but is absent in that of female phalluses [15] (Figure 4).…”

Section: Igf1 and Urethral Closurementioning

confidence: 99%

Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby

Chen

Renfree

2020

Genes

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Congenital anomalies in phalluses caused by endocrine disruptors have gained a great deal of attention due to its annual increasing rate in males. However, the endocrine-driven molecular regulatory mechanism of abnormal phallus development is complex and remains largely unknown. Here, we review the direct effect of androgen and oestrogen on molecular regulation in phalluses using the marsupial tammar wallaby, whose phallus differentiation occurs after birth. We summarize and discuss the molecular mechanisms underlying phallus differentiation mediated by sonic hedgehog (SHH) at day 50 pp and phallus elongation mediated by insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3), as well as multiple phallus-regulating genes expressed after day 50 pp. We also identify hormone-responsive long non-coding RNAs (lncRNAs) that are co-expressed with their neighboring coding genes. We show that the activation of SHH and IGF1, mediated by balanced androgen receptor (AR) and estrogen receptor 1 (ESR1) signalling, initiates a complex regulatory network in males to constrain the timing of phallus differentiation and to activate the downstream genes that maintain urethral closure and phallus elongation at later stages.

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Section: Igf1 and Urethral Closurementioning

confidence: 99%

Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby

Chen

Renfree

2020

Genes

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“…The urogenital system includes the urinary tract: composed of the kidney, the ureter, the bladder, and the urethra; and the reproductive tract: composed of the testes, the accessory glands, and the external genitalia (EXG). Recently, an increasing number of regulatory genes for EXG development has been reported [13][14][15][16][17]. Thus, possible insights gleaned from comparisons between urogenital organogenesis with other medical topics, such as prostate cancer, is valuable.…”

Section: Hedgehog Signaling and Emi In Urogenital Organogenesismentioning

confidence: 99%

“…One of its ligands, Shh, is expressed in the endodermal epithelia of the embryonic urethra [18,19]. The Shh released from the epithelia can regulate the differentiation of the bilateral mesenchyme, the tissue located immediately adjacent to the urethra [15,20,21]. Such regulation of the mesenchyme by epithelial signals is a key event for EXG organogenesis, as loss of this signal leads to the agenesis of the EXG anlage, the genital tubercle (GT) [19].…”

Section: Hedgehog Signaling and Emi In Urogenital Organogenesismentioning

confidence: 99%

“…In mice, EXG development occurs independently of androgen during the early stages. In the male, this is subsequently followed by an androgen-dependent masculinization process [15,88,89]. Robust mouse embryonic GT outgrowth is promoted by testicular androgens, starting from mid-gestation (~E14.0-15.0) until after birth [90].…”

Section: Modulation Of Hedgehog Signaling By Androgen the Male Hormonementioning

confidence: 99%

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Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)

Hyuga

Alcantara

Kajioka

et al. 2019

IJMS

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Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial–mesenchymal interface.

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“…The review by Hyuga et al focusses on early and late stages of GT development in male and female mouse embryos (Hyuga et al, 2019). The authors review their earlier studies on the role of various growth factors (Fibroblast growth factor) and Wnt genes that function during GT formation.…”

mentioning

confidence: 99%

Development of the external genitalia

Cunha

Baskin

2020

Differentiation

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Regulatory roles of epithelial-mesenchymal interaction (EMI) during early and androgen dependent external genitalia development

Cited by 13 publications

References 75 publications

Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby

Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby

Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)

Development of the external genitalia

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