Yao, H. H., Whoriskey, W. & Capel, B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev. 16, 1433-1440

Duke University, Durham, North Carolina, United States
Genes & Development (Impact Factor: 10.8). 07/2002; 16(11):1433-40. DOI: 10.1101/gad.981202
Source: PubMed


Establishment of the steroid-producing Leydig cell lineage is an event downstream of Sry that is critical for masculinization of mammalian embryos. Neither the origin of fetal Leydig cell precursors nor the signaling pathway that specifies the Leydig cell lineage is known. Based on the sex-specific expression patterns of Desert Hedgehog (Dhh) and its receptor Patched 1 (Ptch1) in XY gonads, we investigated the potential role of DHH/PTCH1 signaling in the origin and specification of fetal Leydig cells. Analysis of Dhh(-/-) XY gonads revealed that differentiation of fetal Leydig cells was severely defective. Defects in Leydig cell differentiation in Dhh(-/-) XY gonads did not result from failure of cell migration from the mesonephros, thought to be a possible source of Leydig cell precursors. Nor did DHH/PTCH1 signaling appear to be involved in the proliferation or survival of fetal Leydig precursors in the interstitium of the XY gonad. Instead, our results suggest that DHH/PTCH1 signaling triggers Leydig cell differentiation by up-regulating Steroidogenic Factor 1 and P450 Side Chain Cleavage enzyme expression in Ptch1-expressing precursor cells located outside testis cords.

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Available from: Humphrey Hung-Chang Yao, Mar 17, 2014
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    • "Several genetic modifications have demonstrated FLC as targets of hedgehog signalling (Park et al., 2007). Dhh knockout mice have a reduced number of FLC (Yao et al., 2002), overexpress Gli1 (Kroft et al., 2001) and show constitutive activation of Smo (Barsoum et al., 2013) resulting in FLC hyperplasia. It is possible that the downstream target gene of Dhh signalling in FLC is the orphan nuclear receptor chicken ovalbumin upstream promoter transcription factor II (Coup-tfII), as has been demonstrated in other organs (Krishnan et al., 1997; Xu et al., 2008). "
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    ABSTRACT: BACKGROUND Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed ‘mini-puberty’ precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic–pituitary–testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates.
    Full-text · Article · Feb 2015 · Human Reproduction Update
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    • "DHH is a cell signalling molecule produced by Sertoli cells, and disruption of spermatogenesis and loss of adult-type Leydig cells are reported in DHH-null mice (Clark et al. 2000, Pierucci-Alves et al. 2001, Yao et al. 2002). DHH signalling triggers Leydig cell differentiation by upregulation of CYP11A1 expression because it acts as a positive regulator of steroidproducing Leydig cell differentiation from foetal to adult testes (Yao et al. 2002). In the absence of DHH and PDGFA, adult Leydig cells (ALCs) fail to develop, which can also be related to the failure of stem cell development (Clark et al. 2000, Gnessi et al. 2000, Park et al. 2007). "
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    ABSTRACT: Ectopic autografting of testis tissue is a promising approach for studying testicular development, male germline preservation, and restoration of male fertility. In this study, we examined the fate of various testicular cells in adult mouse testes following ectopic autografting at 1, 2, 4, and 8 weeks post grafting. Histological examination showed no evidence of re-establishment of spermatogenesis in autografts, and progressive degeneration of seminiferous tubules was detected. Expression of germ cell-specific proteins such as POU5F1, DAZL, TNP1, TNP2, PRM1 and PRM2 revealed that, although proliferating and differentiating spermatogenic germ cells such as spermatogonia, spermatocytes, and spermatids could survive in autografts until 4 weeks, only terminally differentiated germ cells such as sperm persisted in autografts until 8 weeks. Presence of Sertoli and peritubular myoid cells, as indicated by expression of WT1 and ACTA2 proteins, respectively, was evident in the autografts until 8 weeks. Interestingly, seminal vesicle weight and serum testosterone level was restored in autografted mice by 8 weeks post grafting. Expression of Leydig cell-specific proteins such as CYP11A1, HSD3B2, and LHCGR showed revival of Leydig cell populations in autografts over time since grafting. Elevated expression of PDGFRA, LIF, DHH, and NEFH in autografts indicated de novo regeneration of LC populations. Autografted adult testis can be used as a model for investigating Leydig cell regeneration, steroidogenesis, and regulation of the intrinsic factors involved in Leydig cell development. The success of this rodent model can have therapeutic applications for adult human males undergoing sterilizing cancer therapy.
    Full-text · Article · Dec 2014 · Reproduction (Cambridge, England)
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    • "Sertoli cells express multiple exclusive markers including Dhh, Kitl, Pdgfa, Claudin and Occludin; therefore, little or no expression of these markers is found in other testis cell types (Bitgood et al., 1996; Morita et al., 1999; Gnessi et al., 2000; Cai et al., 2011). Dhh has been detected in fetal SCs, Leydig and myoid cells, and are essential for the development of Leydig cells (Yao et al., 2002; Kawai et al., 2011). Pdgfa is expressed in both XX and XY gonads 11.5 days post coitus (dpc); by 12.5 dpc, it is strongly expressed in SCs in the seminiferous tubules, whereas its expression in the XX gonad is diminished in mice (Brennan et al., 2003). "
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    ABSTRACT: Melatonin and its receptors are found in the testis of many species, where they mediate testicular functions. The present study aimed to investigate the expression of melatonin receptors (MT1 and MT2) in bovine Sertoli cells (SCs), using reverse transcription polymerase chain reaction (RT-PCR) and western blot. In addition, we assessed the mRNA levels of spermatogenesis-related genes (Real-time PCR) and secretion of inhibin B after treatment with various concentrations (0, 80, 160, and 320 pg/mL) of melatonin at different time points (24, 48, or 72 h). We found that bovine SCs express MT1 and MT2 receptors, which were regulated by melatonin in time- and dose-dependent manners after treatment with melatonin. Exogenous melatonin up-regulated the expression of spermatogenesis-related genes, including Cyclin D1, Cyclin E, Pdgfa, Dhh, Occludin, and Claudin, and decreased the mRNA levels of P21 and Kit1 in a time or dose-dependent manner. Meanwhile, melatonin supplementation significantly affected Inhba, Inhbb and Inha mRNA expression. These findings were consistent with inhibin B levels detected in the culture medium. In conclusion, exogenous melatonin acts via its receptors and appears to play regulatory roles in the development and function of bovine SCs
    Full-text · Article · Jun 2014 · Animal reproduction science
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