Temporal and spatial expression of liver receptor homologue-1 (LRH-1) during embryogenesis suggests a potential role in gonadal development

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Developmental Dynamics (Impact Factor: 2.38). 09/2005; 234(1):159-68. DOI: 10.1002/dvdy.20490
Source: PubMed


Liver receptor homologue-1 (LRH-1), an orphan member of the nuclear receptor family highly expressed in adult mouse ovary, is closely related to steroidogenic factor 1 (SF-1), known to be important in gonadal formation. To analyze the potential role of LRH-1 in gonadal differentiation, we compared LRH-1 and SF-1 expression during mouse embryonic and postnatal development. LRH-1 expression was first detected in the urogenital ridge before sexual determination, in primordial germ cells and surrounding somatic cells; expression persisted after differentiation into testes and ovaries. Of interest, LRH-1 expression declined in the developing ovary and testis at embryonic day 15.5 but increased again just after birth in the ovary in granulosa cells and transiently in oocytes of developing follicles. By comparing and contrasting LRH and SF-1 expression with the two tissue-specific steroidogenic markers, cytochromes P450 aromatase and P450 17alpha-hydroxylase/17,20 lyase, we provide evidence for a potential role for LRH-1 in gonadal development, the initiation of folliculogenesis and regulation of estrogen biosynthesis within the ovary.

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    • "Real-time PCR was performed to determine the level of expression of mRNA for Cyp17a1 (cytochrome P450, family 17, subfamily a, polypeptide 1) and Cyp19a1 (cytochrome P450, family 19, subfamily a, polypeptide 1; aromatase) in the ovaries of each mouse that was sacrificed (Figure 1). Analysis of the level of mRNA for these two steroidogenic genes was used as another means of confirmation that the estrous cycle of each mouse had been staged correctly, as described by others (Soumano et al. 1996; Hinshelwood et al. 2005). Real-time PCR was performed using SYBR Green PCR Master Mix (Bio-Rad, Hercules, CA) and gene specific primer pairs (Cyp17a1 forward 5′-TGG TCA TAT GCA TGC CAA CT-3′ and reverse 5′-GAG CGT AGA CAG ATC TCG GG-3′; Cyp19a1 forward 5′-GTC CTG GCT ACT GTC TGG GA-3′ and reverse 5′-CAA ATG CTG CTT GAT GGA CT-3′) on a Bio- Rad IQ5 system, as described previously (Al-Alem et al. 2007; Bridges et al. 2010; Jeoung et al. 2010). "
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    ABSTRACT: The oviduct is a dynamic structure whose function relies upon cyclic changes in the morphology of both ciliated and secretory luminal epithelial cells. Unfortunately, infection of these epithelial cells by sexually transmitted pathogens can lead to pelvic inflammatory disease, ectopic pregnancies and infertility. The disruption of normal, cyclic apoptosis in the oviducal epithelium appears to be a causal factor of oviducal pathology and therefore, these pathways represent a potential target for diagnosis and therapeutic intervention. The objective of this study was to determine the pattern of expression for apoptotic genes in the oviduct of the naturally cycling mouse, generating fundamental information that can be applied to the development of animal models for research and the identification of targets for disease intervention. Whole oviducts were collected from regular cycling mice killed at 1p.m. on each day of the oestrous cycle and the expression of 84 apoptotic genes determined by targeted PCR super-array. Intact and cleaved caspases were then evaluated by western blotting. The expression of mRNA for genes classified as pro-apoptotic (Bad, Bak1 and Bok) and anti-apoptotic (Bag3, Bnip2 and Xiap) was regulated by day (P < 0.05). Differences in the temporal expression of several p53-related genes (Trp53bp2, Trp53inp1 and Trp73), those specific to the TNF superfamily (Tnfrsf10 and Tnfsf10b) and one caspase (Casp14) were also observed (P < 0.05). The cleaved forms of Caspases-3, -6 and -12 were all detected throughout the oestrous cycle. These results represent the first pathway-wide analysis of apoptotic gene expression in the murine oviduct.
    Reproduction Fertility and Development 06/2011; 23(5):638-44. DOI:10.1071/RD11011 · 2.40 Impact Factor
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    • "The balance between cholesterol use in steroidogenesis and degradation in the bile acid pathway is not known, but most likely there is a fine balance which may prove crucial to oocyte maturation. In support of this hypothesis are recently published experimental data with rodents where a role for LRH-1 in steroidogenesis, gonadal development, aromatase expression, and progesterone biosynthesis was clearly documented [17], [28]. Another recent study has linked LRH-1 with ovulation in a rodent model, demonstrating that this receptor is required for rodent ovarian follicular development and fertility [17]. "
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    ABSTRACT: Bile acids, end products of the pathway for cholesterol elimination, are required for dietary lipid and fat-soluble vitamin absorption and maintain the balance between cholesterol synthesis in the liver and cholesterol excretion. They are composed of a steroid structure and are primarily made in the liver by the oxidation of cholesterol. Cholesterol is also highly abundant in the human ovarian follicle, where it is used in the formation of the sex steroids. Here we describe for the first time evidence that all aspects of the bile acid synthesis pathway are present in the human ovarian follicle, including the enzymes in both the classical and alternative pathways, the nuclear receptors known to regulate the pathway, and the end product bile acids. Furthermore, we provide functional evidence that bile acids are produced by the human follicular granulosa cells in response to cholesterol presence in the culture media. These findings establish a novel pathway present in the human ovarian follicle that has the capacity to compete directly with sex steroid synthesis.
    PLoS ONE 10/2009; 4(10):e7333. DOI:10.1371/journal.pone.0007333 · 3.23 Impact Factor
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    ABSTRACT: Germ cell tumors occur both in the gonads of both sexes and in extra-gonadal sites during adoles-cence and early adulthood. Malignant ovarian germ cell tumors are rare neoplasms accounting for less than 5% of all cases of ovarian malignancy. In contrast, testicular cancer is the most common malignancy among young males. Most of patients survive the disease. Prognostic factors of gonadal germ cell tumors include histology, clinical stage, size of the primary tumor and residua, and levels of tumor markers. Germ cell tumors include heterogeneous histological subgroups. The most common subgroup includes germinomas (ovarian dysgerminoma and testicular seminoma); other subgroups are yolk sac tumors, embryonal carcinomas, immature teratomas and mixed tumors. The origin of germ cell tumors is most likely primordial germ cells. Factors behind germ cell tumor development and differentiation are still poorly known. The purpose of this study was to define novel diagnostic and prognostic factors for malignant gonadal germ cell tumors. In addition, the aim was to shed further light into the molecular mechanisms regulating gonadal germ cell tumorigenesis and differentiation by studying the roles of GATA transcription factors, pluripotent factors Oct-3/4 and AP-2γ, and estrogen receptors. This study revealed the prognostic value of CA-125 in malignant ovarian germ cell tumors. In addition advanced age and residual tumor had more adverse outcome. Several novel markers for histological diagnosis were defined. In the fetal development transcription factor GATA-4 was expressed in early fetal gonocytes and in testicular carcinoma precursor cells. In addition, GATA-4 was expressed in both gonadal germinomas, thus it may play a role in the development and differentiation of the germinoma tumor subtype. Pluripotent factors Oct-3/4 and AP-2γ were expressed in dysgerminomas, thus they could be used in the differential diagnosis of the germ cell tumors. Malignant ovarian germ cell tumors expressed estrogen receptors and their co-regulator SNURF. In addition, estrogen receptor expression was up-regulated by estradiol stimulation. Thus, gonadal steroid hormone burst in puberty may play a role in germ cell tumor development in the ovary. This study shed further light in to the molecular pathology of malignant gonadal germ cell tumors. In addition, some novel diagnostic and prognostic factors were defined. This data may be used in the differential diagnosis of germ cell tumor patients. Kivessyöpä on nuorten miesten yleisin kasvain. Näistä kasvaimista suurin osa on itusolukasvaimia ja niiden esiintyvyys on viimevuosina merkittävästi lisääntynyt. Munasarjan vastaavat pahanlaatuiset itusolukasvaimet ovat harvinaisia, mutta nuorilla fertiili-ikäisillä naisilla yleisiä kasvaimia. Kiveksen ja munasarjan kasvaimet muistuttavat histologisesti toisiaan, mutta ovat hyvin heterogeeninen kasvainryhmä. Itusolukasvaimilla on kehityksellinen yhteys esi-itusoluihin ja kantasoluihin, mutta näiden kasvainten kehitysbiologiasta ja erilaistumisesta tiedetään varsin vähän. Tämän väitöskirjatutkimuksen tavoitteena oli löytää uusia kasvainmerkkiaineita pahanlaatuisten itusolukasvainten diagnosointiin ja seurantaan. Lisäksi tutkittiin itusolukasvainten kehittymiseen ja erilaistumiseen vaikuttavia tekijöitä. Itusolukasvaimet kehittyvät esi-itusoluista. Sikiökehityksen aikana osalla transkriptiotekijöistä ja näiden yhteydessä vaikuttavista tekijöistä on tärkeä rooli itusolujen pluripotenssin ylläpitämisessä. Näillä tekijöillä on todennäköisesti merkitystä myös itusolukasvainten synnyssä. Tässä väitöskirjatutkimuksessa löydettiin itusolukasvainten uusia ennusteellisia ja diagnostisia tekijöitä. Munasarjan epiteliaalisen syövän diagnosoinnissa käytetty kasvainmerkkiaine CA-125 osoittautui ennusteelliseksi tekijäksi myös munasarjan itusolukasvaimissa. Pluripotentit tekijät AP-2gamma sekä Oct-3/4 ilmentyivät munasarjan dysgerminoomissa muiden alatyyppien ollessa negatiivisia näiden tekijöiden suhteen. Näitä merkkiaineita voidaan siten käyttää kasvainten histologiseen diagnosointiin. Transkriptiotekijä GATA-4 ilmentyi sikiön kehityksen aikana kiveksessä hyvin varhaisen vaiheen itusoluissa. Toisaalta GATA-4 ei ilmentynyt aikuisen kiveksen itusoluissa, mutta ilmentyi kiveskasvainten esiasteissa. GATA-4 ilmentyi myös molempien sukurauhasten germinooman tyypin kasvaimissa. GATA-4 tekijällä voi olla rooli kiveskasvainten esiasteiden synnyssä sekä kasvainten histologisessa erilaistumisessa. Munasarjan kaikki histologiset alatyypit ilmensivät estrogeeni-reseptoreita ja näiden säätelijää SNURF-proteiinia. Lisäksi estrogeeni-reseptoreiden geeniekspressio lisääntyi estradioli-käsittelyllä. Tämä voi kertoa murrosiän estrogeenimyrskyn mahdollisesta vaikutuksesta munasarjan itusolukasvainten syntyyn. Tutkimuksessa löydettiin uusia merkkiaineita harvinaisten itusolukasvainten erotusdiagnostiikkaan. Lisäksi kartoitettiin kasvainten biologiaan ja erilaistumiseen liittyviä tekijöitä. Tutkimuksella on kliinistä merkitystä nuorten fertiili-ikäisten itusolukasvainpotilaiden taudin diagnosoinnissa ja seurannassa.
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