Temporal and spatial dissection of Shh signaling in genital tubercle development

Lin, Congxing; Yin, Yan; Veith, G; Fisher, Alan E.; Long, Fanxin; Ma, Liang

doi:10.1242/dev.039768

Cited by 65 publications

(99 citation statements)

References 39 publications

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“…By contrast, conditional deletion of AR in urethral epithelial cells had no affect on genital development or sexual differentiation, suggesting that cell death at the ventral ectoderm-endoderm junction may be mediated via the adjacent mesenchyme rather than by a cell autonomous response of urethral endodermal or ventral ectodermal cells to AR activity. Our hypothesis that AR acts primarily on genital mesenchyme and that a relay mechanism mediates its effect on adjacent epithelia is supported by evidence that androgen signaling regulates expression of genes in the Fgf, Bmp, and Hh pathways, which are known to control apoptosis during early development of the genital tubercle (35,37,39,40,43).…”

Section: Discussionmentioning

confidence: 76%

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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.

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: 76%

“…Hedgehog signaling is required for patterning and outgrowth of the genital tubercle at early stages and for sexual differentiation at later stages of development (36,37,43). Deletion of Shh at E10.5 results in agenesis of external genitalia, and deletion of Shh after E13.5 cause hypospadias (36).…”

Section: Discussionmentioning

confidence: 99%

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.

129

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“…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%

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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“…1C,H and Fig. 2C; Nievelstein et al, 1998;Perriton et al, 2002;Sasaki et al, 2004;Seifert et al, 2008Seifert et al, , 2009aLin et al, 2009;Ng et al, 2014;Ching et al, 2014;Miyagawa et al, 2014).…”

Section: Introductionunclassified

An illustrated anatomical ontology of the developing mouse lower urogenital tract

et al. 2015

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Malformation of the urogenital tract represents a considerable paediatric burden, with many defects affecting the lower urinary tract (LUT), genital tubercle and associated structures. Understanding the molecular basis of such defects frequently draws on murine models. However, human anatomical terms do not always superimpose on the mouse, and the lack of accurate and standardised nomenclature is hampering the utility of such animal models. We previously developed an anatomical ontology for the murine urogenital system. Here, we present a comprehensive update of this ontology pertaining to mouse LUT, genital tubercle and associated reproductive structures (E10.5 to adult). Ontology changes were based on recently published insights into the cellular and gross anatomy of these structures, and on new analyses of epithelial cell types present in the pelvic urethra and regions of the bladder. Ontology changes include new structures, tissue layers and cell types within the LUT, external genitalia and lower reproductive structures. Representative illustrations, detailed text descriptions and molecular markers that selectively label muscle, nerves/ganglia and epithelia of the lower urogenital system are also presented. The revised ontology will be an important tool for researchers studying urogenital development/malformation in mouse models and will improve our capacity to appropriately interpret these with respect to the human situation.

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Temporal and spatial dissection of Shh signaling in genital tubercle development

Cited by 65 publications

References 39 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

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

An illustrated anatomical ontology of the developing mouse lower urogenital tract

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