1,721,034 research outputs found
Development of the adreno-genital system : Female sex determination, ovarian and adrenal gland ontogeny regulated by <em>Wnt-4</em> in mice
Get PDFAbstractAlthough the genetic sex of an embryo is determined at conception by the presence or absence of the Y chromosome, both females and males have bipotential, undifferentiated gonads early in their development. Genes and testicular hormones direct differentiation into either testes or ovaries. The first relevant gene to be identified was the Y-linked master regulatory gene, SRY, since when several other genes have been found to be of importance for sex determination.The primary aim here was to identify the role of Wnt-4 in the development of the gonad and adrenal gland. Wnt-4 was found to be expressed in the developing gonad, the Müllerian duct and the adrenal gland, in addition to the kidney, pituitary gland and mammary gland as observed earlier. Expression in the gonad was found to be regulated in a sex-specific manner. After sex determination Wnt-4 was downregulated in the testis, but the expression persisted until birth in the ovary. Wnt-4-deficient female mice demonstrated a partial female-to-male sex reversal and a reduction in the number of oocytes, while the Müllerian duct was absent from both sexes. Lack of Wnt-4 in the adrenal gland led to reduced aldosterone production, indicating abnormal development of the zona glomerulosa. Flutamide administration to pregnant Wnt-4 heterozygote females was shown to partially restore the sex reversal.The results suggest that female development is not a default pathway but needs active signalling, in which Wnt-4 plays an essential role. Academic Dissertation to be presented with the assent of the Faculty of Science, University of Oulu, for public discussion in Raahensali (Auditorium L 10), Linnanmaa, on November 8th, 2002, at 10 a.m.Abstract
Although the genetic sex of an embryo is determined at conception by the presence or absence of the Y chromosome, both females and males have bipotential, undifferentiated gonads early in their development. Genes and testicular hormones direct differentiation into either testes or ovaries. The first relevant gene to be identified was the Y-linked master regulatory gene, SRY, since when several other genes have been found to be of importance for sex determination.
The primary aim here was to identify the role of Wnt-4 in the development of the gonad and adrenal gland. Wnt-4 was found to be expressed in the developing gonad, the Müllerian duct and the adrenal gland, in addition to the kidney, pituitary gland and mammary gland as observed earlier. Expression in the gonad was found to be regulated in a sex-specific manner. After sex determination Wnt-4 was downregulated in the testis, but the expression persisted until birth in the ovary. Wnt-4-deficient female mice demonstrated a partial female-to-male sex reversal and a reduction in the number of oocytes, while the Müllerian duct was absent from both sexes. Lack of Wnt-4 in the adrenal gland led to reduced aldosterone production, indicating abnormal development of the zona glomerulosa. Flutamide administration to pregnant Wnt-4 heterozygote females was shown to partially restore the sex reversal.
The results suggest that female development is not a default pathway but needs active signalling, in which Wnt-4 plays an essential role
Luteinizing hormone receptor : Expression and post-translational regulation of the rat receptor and its ectodomain splice variant
Get PDFAbstractThe luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) that has a large N-terminal ligand binding ectodomain. The LHR ectodomain splice variant, expressed concomitantly with the full-length LHR in tissues, has an unknown biological function. GPCRs are a major pharmacological target, however, very little is known about the intracellular regulation of these receptors. In the present work, expression and maturation of the rat LHR and its variant were elucidated using both tissues and heterologous expression systems. A special effort was made to identify the role of developmental stage and tissue type on the LHR maturation and to find out about the molecular role of the ectodomain splice variant.We found two sites of localization for the receptor, namely the sensory system and urogenital tissues. This was demonstrated at mRNA and protein level and by rat LHR promoter-driven β-galactosidase (β-Gal) expression in the mice. In neurons, the β-Gal co-localized with the cytochrome P450 side chain cleavage enzyme, which may indicate a novel role in the neurosteroid synthesis.The neuronal LHR was expressed in the mature and immature protein forms in both developing and adult tissues, being able to bind hormone with similar high-affinity as gonadal receptors. In contrast, only immature receptors were detected in the fetal rat urogenital structures. A significant novel finding was substantial upregulation of the LHR in pregnant female rat adrenal glands and kidneys at a time that coincides with the differentiation of the fetal urogenital tissues.The mice overexpressing the ectodomain splice variant showed interference in pituitary-gonadal functions and morphological changes in the urogenital tissues. The studies showed that the variant was an endoplasmic reticulum (ER)-retained soluble protein. It accumulated in juxtanuclear regions of the ER together with ER folding chaperones and was a substrate for ER associated degradation (ERAD). The co-expression of the variant with the full-length receptor decreased the amount of receptors and misrouted them to the juxtanuclear ER subcompartment.Taken together, we suggest that the maturation of the LHR protein is developmentally and physiologically regulated at the post-translational level in tissues. The LHR ectodomain splice variant possibly modulates post-translationally the number of full-length receptors through physiological signals. Our observation of the chaperone and protein accumulation into a specific ER subcompartment may represent a protein quality control holding compartment for inefficiently/misfolded ERAD substrates.Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium 5 of the Institute of Dentistry, on November 25th, 2005, at 12 noonAbstract
The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) that has a large N-terminal ligand binding ectodomain. The LHR ectodomain splice variant, expressed concomitantly with the full-length LHR in tissues, has an unknown biological function. GPCRs are a major pharmacological target, however, very little is known about the intracellular regulation of these receptors. In the present work, expression and maturation of the rat LHR and its variant were elucidated using both tissues and heterologous expression systems. A special effort was made to identify the role of developmental stage and tissue type on the LHR maturation and to find out about the molecular role of the ectodomain splice variant.
We found two sites of localization for the receptor, namely the sensory system and urogenital tissues. This was demonstrated at mRNA and protein level and by rat LHR promoter-driven β-galactosidase (β-Gal) expression in the mice. In neurons, the β-Gal co-localized with the cytochrome P450 side chain cleavage enzyme, which may indicate a novel role in the neurosteroid synthesis.
The neuronal LHR was expressed in the mature and immature protein forms in both developing and adult tissues, being able to bind hormone with similar high-affinity as gonadal receptors. In contrast, only immature receptors were detected in the fetal rat urogenital structures. A significant novel finding was substantial upregulation of the LHR in pregnant female rat adrenal glands and kidneys at a time that coincides with the differentiation of the fetal urogenital tissues.
The mice overexpressing the ectodomain splice variant showed interference in pituitary-gonadal functions and morphological changes in the urogenital tissues. The studies showed that the variant was an endoplasmic reticulum (ER)-retained soluble protein. It accumulated in juxtanuclear regions of the ER together with ER folding chaperones and was a substrate for ER associated degradation (ERAD). The co-expression of the variant with the full-length receptor decreased the amount of receptors and misrouted them to the juxtanuclear ER subcompartment.
Taken together, we suggest that the maturation of the LHR protein is developmentally and physiologically regulated at the post-translational level in tissues. The LHR ectodomain splice variant possibly modulates post-translationally the number of full-length receptors through physiological signals. Our observation of the chaperone and protein accumulation into a specific ER subcompartment may represent a protein quality control holding compartment for inefficiently/misfolded ERAD substrates
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Apoptosis-regulating factors in developing and adult ovaries
Get PDFAbstractApoptosis plays a crucial part in human ovarian function from fetal development to the end of reproductive potential. Failures in the regulation of ovarian apoptosis are associated with many pathological conditions such as premature ovarian insufficiency, infertility and cancer. The purpose of the present study was to analyze the factors regulating cell survival in human fetal and adult ovaries. The fetus is exposed to maternal- and placental-derived estrogens and insufficient estrogen action has destructive effects on rodent ovarian development. We detected estrogen receptors and estrogen-converting enzymes in human fetal ovaries after primordial follicle formation, indicating that estrogens participate in human fetal ovarian development, especially after folliculogenesis. The WNT4 gene is crucial for female sexual differentiation, follicle formation and oocyte survival. We detected WNT4 in follicular cells of fetal and adult human ovaries. In addition, Wnt4- knockout mice demonstrated a dramatic loss of oocytes before birth. However, no changes were detected in protein expression patterns of common apoptosis-related proteins. The results support the possible role of WNT4 in human ovarian function and strengthen previous knowledge on the antiapoptotic role of Wnt4. Apoptosis signaling is mediated by extracellular- and mitochondria-associated- pathways, ending in caspase cascade activation and fragmentation of cellular structures. In the present study we analyzed the expression of several apoptosis-related factors and detected TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries. In addition, TRAIL was found to be a potent and rapid inducer of human granulosa tumor cell (KGN) apoptosis. Lentiviral downregulation of Bok or Bcl-XL protein expression in KGN cells also resulted in significant changes in cell vulnerability to apoptosis. The results show for the first time the spatiotemporal expression patterns of TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries and suggest an important functional role of TRAIL, Bok and Bcl-XL in regulation of human ovarian apoptosis. The present study offers novel information on the expression and function of cell survival factors in human ovaries. These new findings open possibilities for future clinical research in attempts to understand and treat ovarian diseases caused by imbalanced regulatory pathways of apoptosis. Academic dissertation to be presented with the assent of the Faculty of Medicine of the University of Oulu for public defence in Auditorium 4 of Oulu University Hospital, on 26 November 2010, at 12 noonAbstract
Apoptosis plays a crucial part in human ovarian function from fetal development to the end of reproductive potential. Failures in the regulation of ovarian apoptosis are associated with many pathological conditions such as premature ovarian insufficiency, infertility and cancer. The purpose of the present study was to analyze the factors regulating cell survival in human fetal and adult ovaries.
The fetus is exposed to maternal- and placental-derived estrogens and insufficient estrogen action has destructive effects on rodent ovarian development. We detected estrogen receptors and estrogen-converting enzymes in human fetal ovaries after primordial follicle formation, indicating that estrogens participate in human fetal ovarian development, especially after folliculogenesis.
The WNT4 gene is crucial for female sexual differentiation, follicle formation and oocyte survival. We detected WNT4 in follicular cells of fetal and adult human ovaries. In addition, Wnt4- knockout mice demonstrated a dramatic loss of oocytes before birth. However, no changes were detected in protein expression patterns of common apoptosis-related proteins. The results support the possible role of WNT4 in human ovarian function and strengthen previous knowledge on the antiapoptotic role of Wnt4.
Apoptosis signaling is mediated by extracellular- and mitochondria-associated- pathways, ending in caspase cascade activation and fragmentation of cellular structures. In the present study we analyzed the expression of several apoptosis-related factors and detected TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries. In addition, TRAIL was found to be a potent and rapid inducer of human granulosa tumor cell (KGN) apoptosis. Lentiviral downregulation of Bok or Bcl-XL protein expression in KGN cells also resulted in significant changes in cell vulnerability to apoptosis. The results show for the first time the spatiotemporal expression patterns of TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries and suggest an important functional role of TRAIL, Bok and Bcl-XL in regulation of human ovarian apoptosis.
The present study offers novel information on the expression and function of cell survival factors in human ovaries. These new findings open possibilities for future clinical research in attempts to understand and treat ovarian diseases caused by imbalanced regulatory pathways of apoptosis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Wnt4-signaloinnin merkitys nisäkkäiden sukupuolen määräytymisessä, munasarjojen kehittymisessä sekä naaraan sukupuolitiehyitten erilaistumisessa
No full textAbstractMammalian female sex development was considered a default developmental pathway. However, the deletion of the Wnt4 gene, a member of the Wnt family of secreted signals, was shown to reverse the sex of XX female mouse embryo and caused exhibition of certain male characteristics. This indicated that the female sexual development cannot be default but depends on active signaling and cell-cell interaction.The aim of the current study was to reveal the functional role of the Wnt4 gene in the control of sex determination, ovariogenesis and female sex duct formation.This study demonstrates that testosterone is produced by the ovary of Wnt4-deficient female embryos. The inhibition of androgen action by an antiandrogen, flutamide, during gestation leads to complete degeneration of the Wolffian ducts in 80% of the Wnt4 mutant females. This suggests that testosterone is the possible mediator of the masculinization phenotype in Wnt4-deficient females. Wnt4 is expressed by ovarian somatic cells, which are vital for the control of female germline development. This work has shown that Wnt4 is the factor maintaining germ cell cysts, cell-cell interaction and early follicular gene expression. In addition, the findings indicate a critical role for Wnt4/5a signaling in meiosis. Our research has proven that Wnt4 has roles during postnatal ovary development as its defective signaling leads to premature ovarian failure associated with diminished Amh levels, defective basement membrane and cell polarization.The Mullerian duct, the anlagen of oviduct, uterus and upper part of vagina, does not form in Wnt4-deficient females. This study indicates that Wnt4 is needed for migration initiation and maintenance during Mullerian duct formation prenatally. During the postnatal uterine differentiation Wnt4 is essential for endometrial gland formation.The present study provides new evidence for Wnt4 function during embryonic and adult female sexual differentiation.TiivistelmäNisäkkäiden naaraspuolista kehitystä pidettiin aiemmin sukupuolisen erilaistumiskehityksen oletusarvona. Signaloivien proteiinien Wnt-perheeseen kuuluvan Wnt4-geenin puutteen todettiin kuitenkin johtavan XX naarasalkion sukupuolen kääntymisen koiraaksi sekä aiheuttavan tiettyjä koiraille ominaisia piirteitä. Tämä osoitti, ettei naaraspuolinen kehitys ole oletusarvo, vaan se riippuu aktiivisesta signaloinnista ja solujen välisestä interaktiosta.Tämän väitöstutkimuksen tarkoitus oli selvittää Wnt4-geenin roolia sukupuolen määräytymisessä, munasarjojen kehittymisessä sekä naaraan sukupuolitiehyitten muodostumisessa.Tutkimuksessa osoitettiin, että munasarjat tuottavat testosteronia niillä naaraspuolisilla alkioilla, joilta puuttuu Wnt4-geeni. 80 prosentilla naaraista, joilla on Wnt4-geenin puute, androgeenivaikutuksen esto raskauden aikana annettavalla antiandrogeenilla, flutamidilla, estää sukupuolen vaihtumisen fenotyypin. Tämä viittaa siihen, että testosteroni toimii mahdollisena koiraan fenotyypin välittäjänä naarailla, joilta puuttuu Wnt4-geeni. Wnt4 ilmentyy munasarjojen somaattisissa soluissa, jotka ovat tärkeitä naaraspuolisen ituradan kehityksen säätelyn kannalta. Väitöstutkimus osoittaa, että Wnt4 on itusoluryppäitä, solujen välistä interaktiota sekä varhaista follikkeligeeni-ilmentymistä ylläpitävä tekijä. Tulokset osoittavat myös, että Wnt4/5a -signaloinnilla on tärkeä rooli meioosissa. Tutkimus osoittaa lisäksi, että Wnt4 vaikuttaa munasarjojen kehitykseen myös syntymän jälkeen. Puutteellinen signalointi alentaa Anti-Müllerian hormonin tasoa, heikentää tyvikalvoa ja vähentää solujen polarisaatiota, joka johtaa ennenaikaiseen munasarjojen toiminnan hiipumiseen.Müllerin tiehyet, joista myöhemmin kehittyvät munanjohtimet, kohtu ja vaginan yläosa, jäävät kokonaan muodostumatta naarailla, joilta puuttuu Wnt4-geeni. Tulokset viittaavat siihen, että Wnt4 on tarpeen alkioaikaiseen Müllerin tiehyen muodostavien solujen liikkeellelähtöön ja ylläpitoon. Wnt4:llä on myös keskeinen rooli kohturauhasten muodostumisessa sukukypsyyden saavuttamisen aikana ja sen jälkeen.Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in the Auditorium of Kastelli Research Centre (Aapistie 1), on 30 May 2014, at 12 noonAbstract
Mammalian female sex development was considered a default developmental pathway. However, the deletion of the Wnt4 gene, a member of the Wnt family of secreted signals, was shown to reverse the sex of XX female mouse embryo and caused exhibition of certain male characteristics. This indicated that the female sexual development cannot be default but depends on active signaling and cell-cell interaction.
The aim of the current study was to reveal the functional role of the Wnt4 gene in the control of sex determination, ovariogenesis and female sex duct formation.
This study demonstrates that testosterone is produced by the ovary of Wnt4-deficient female embryos. The inhibition of androgen action by an antiandrogen, flutamide, during gestation leads to complete degeneration of the Wolffian ducts in 80% of the Wnt4 mutant females. This suggests that testosterone is the possible mediator of the masculinization phenotype in Wnt4-deficient females. Wnt4 is expressed by ovarian somatic cells, which are vital for the control of female germline development. This work has shown that Wnt4 is the factor maintaining germ cell cysts, cell-cell interaction and early follicular gene expression. In addition, the findings indicate a critical role for Wnt4/5a signaling in meiosis. Our research has proven that Wnt4 has roles during postnatal ovary development as its defective signaling leads to premature ovarian failure associated with diminished Amh levels, defective basement membrane and cell polarization.
The Mullerian duct, the anlagen of oviduct, uterus and upper part of vagina, does not form in Wnt4-deficient females. This study indicates that Wnt4 is needed for migration initiation and maintenance during Mullerian duct formation prenatally. During the postnatal uterine differentiation Wnt4 is essential for endometrial gland formation.
The present study provides new evidence for Wnt4 function during embryonic and adult female sexual differentiation.Tiivistelmä
Nisäkkäiden naaraspuolista kehitystä pidettiin aiemmin sukupuolisen erilaistumiskehityksen oletusarvona. Signaloivien proteiinien Wnt-perheeseen kuuluvan Wnt4-geenin puutteen todettiin kuitenkin johtavan XX naarasalkion sukupuolen kääntymisen koiraaksi sekä aiheuttavan tiettyjä koiraille ominaisia piirteitä. Tämä osoitti, ettei naaraspuolinen kehitys ole oletusarvo, vaan se riippuu aktiivisesta signaloinnista ja solujen välisestä interaktiosta.
Tämän väitöstutkimuksen tarkoitus oli selvittää Wnt4-geenin roolia sukupuolen määräytymisessä, munasarjojen kehittymisessä sekä naaraan sukupuolitiehyitten muodostumisessa.
Tutkimuksessa osoitettiin, että munasarjat tuottavat testosteronia niillä naaraspuolisilla alkioilla, joilta puuttuu Wnt4-geeni. 80 prosentilla naaraista, joilla on Wnt4-geenin puute, androgeenivaikutuksen esto raskauden aikana annettavalla antiandrogeenilla, flutamidilla, estää sukupuolen vaihtumisen fenotyypin. Tämä viittaa siihen, että testosteroni toimii mahdollisena koiraan fenotyypin välittäjänä naarailla, joilta puuttuu Wnt4-geeni. Wnt4 ilmentyy munasarjojen somaattisissa soluissa, jotka ovat tärkeitä naaraspuolisen ituradan kehityksen säätelyn kannalta. Väitöstutkimus osoittaa, että Wnt4 on itusoluryppäitä, solujen välistä interaktiota sekä varhaista follikkeligeeni-ilmentymistä ylläpitävä tekijä. Tulokset osoittavat myös, että Wnt4/5a -signaloinnilla on tärkeä rooli meioosissa. Tutkimus osoittaa lisäksi, että Wnt4 vaikuttaa munasarjojen kehitykseen myös syntymän jälkeen. Puutteellinen signalointi alentaa Anti-Müllerian hormonin tasoa, heikentää tyvikalvoa ja vähentää solujen polarisaatiota, joka johtaa ennenaikaiseen munasarjojen toiminnan hiipumiseen.
Müllerin tiehyet, joista myöhemmin kehittyvät munanjohtimet, kohtu ja vaginan yläosa, jäävät kokonaan muodostumatta naarailla, joilta puuttuu Wnt4-geeni. Tulokset viittaavat siihen, että Wnt4 on tarpeen alkioaikaiseen Müllerin tiehyen muodostavien solujen liikkeellelähtöön ja ylläpitoon. Wnt4:llä on myös keskeinen rooli kohturauhasten muodostumisessa sukukypsyyden saavuttamisen aikana ja sen jälkeen
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