Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs

Huang, Chen-Che Jeff; Yao, Hisayuki

doi:10.1002/mrd.21174

Cited by 29 publications

(20 citation statements)

References 70 publications

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“…These tissue-specific ligands are believed to act upon the respective Hh-responding cells to regulate their differentiation [37]. Beyond the conversion of cholesterol to steroids in the trophoblasts as reported here, Hh signaling has been implicated in hormonal production by other cells and tissues.…”

Section: Discussionmentioning

confidence: 94%

Hedgehog signaling stimulates the conversion of cholesterol to steroids

Tang

Pan

Luo

et al. 2015

Cellular Signalling

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Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2. Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase. Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.

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Section: Discussionmentioning

confidence: 94%

Hedgehog signaling stimulates the conversion of cholesterol to steroids

Tang

Pan

Luo

et al. 2015

Cellular Signalling

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“…However, this lack of FLC differentiation could also be a result of the mutant testis lacking a required signaling factor: The Pdgfra À/À testis also displays impaired proliferation of Sertoli cells and mesonephric cell migration, and it has been suggested that this Leydig cell phenotype is secondary to Sertoli cell function (Barsoum and Yao 2010). As discussed previously, the early Sertoli cell marker Dhh has been proposed to act as a paracrine trigger for FLC differentiation, given that Leydig cell differentiation is initiated in the fetal ovary as a result of ectopic DHH expression (Barsoum et al 2009;Huang and Yao 2010). Although not conclusive, these observations suggest that hedgehog signaling is responsible for inducing differentiation of multipotent precursor cells present in the gonad interstitium and common to nascent testes and ovaries.…”

Section: Flc Origin and Differentiationmentioning

confidence: 95%

Building the mammalian testis: origins, differentiation, and assembly of the component cell populations

2013

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Development of testes in the mammalian embryo requires the formation and assembly of several cell types that allow these organs to achieve their roles in male reproduction and endocrine regulation. Testis development is unusual in that several cell types such as Sertoli, Leydig, and spermatogonial cells arise from bipotential precursors present in the precursor tissue, the genital ridge. These cell types do not differentiate independently but depend on signals from Sertoli cells that differentiate under the influence of transcription factors SRY and SOX9. While these steps are becoming better understood, the origins and roles of many testicular cell types and structures—including peritubular myoid cells, the tunica albuginea, the arterial and venous blood vasculature, lymphatic vessels, macrophages, and nerve cells—have remained unclear. This review synthesizes current knowledge of how the architecture of the testis unfolds and highlights the questions that remain to be explored, thus providing a roadmap for future studies that may help illuminate the causes of XY disorders of sex development, infertility, and testicular cancers.

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“…Sertoli cells express Dhh ( 120 ) throughout embryonic development until the adult stage ( 121 ). The Hh receptor Ptch1 is expressed in interstitial cells, including peritubular myoid cells, Leydig cells, and endothelial cells ( 120 , 122 ).…”

Section: Role Of Hedgehog Signaling In Steroidogenic Tissuesmentioning

confidence: 99%

Hedgehog Signaling and Steroidogenesis

Finco

LaPensee²,

Krill

et al. 2015

Annu. Rev. Physiol.

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Since its discovery nearly 30 years ago, the Hedgehog (Hh) signaling pathway has been shown to be pivotal in many developmental and pathophysiological processes in several steroidogenic tissues, including the testis, ovary, adrenal cortex, and placenta. New evidence links the evolutionarily conserved Hh pathway to the steroidogenic organs, demonstrating how Hh signaling can influence their development and homeostasis and can act in concert with steroids to mediate physiological functions. In this review, we highlight the role of the components of the Hh signaling pathway in steroidogenesis of endocrine tissues.

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Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs

Cited by 29 publications

References 70 publications

Hedgehog signaling stimulates the conversion of cholesterol to steroids

Hedgehog signaling stimulates the conversion of cholesterol to steroids

Building the mammalian testis: origins, differentiation, and assembly of the component cell populations

Hedgehog Signaling and Steroidogenesis

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