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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit ligand (KL), a ligand for the c-kit protooncogene receptor tyrosine kinase, is an important regulator of germ cell development in rodent gonads. However, no information about the role of KL in the ovaries of women or higher primates has been available. We studied the expression of KL messenger RNA (mRNA) in human ovaries and the effect of purified hCG and recombinant human FSH (rhFSH) on KL mRNA steady state levels in cultures of human granulosa-luteal (GL) cells obtained at oocyte harvest for in vitro fertilization. KL complementary DNA was generated by reverse transcription-polymerase chain reaction from human ovarian tissue RNA. Two alternatively spliced KL transcripts encoding 248-amino acid (aa) and 220-aa membrane-associated KL proteins were observed in GL cells and ovarian tissue. In Northern blot analysis of human ovarian and GL cell RNA, a major transcript of approximately 6.0 kilobases was detected. Specific mRNA transcripts for KL were detected in dot blot filter hybridization analyses, and the steady state levels of these mRNAs were lowered in cultured GL cells by both gonadotropins in a distinct time- and concentration-dependent manner. The KL mRNA levels of untreated and hCG- or rhFSH-stimulated GL cells were determined at 2- to 3-day intervals between days 2-10 of culture. An 8-h treatment with hCG was shown to decrease KL mRNA levels on days 2, 3, 5, and 7 of culture, whereas rhFSH decreased KL mRNA levels on days 5 and 7 of culture. Time-course and concentration-dependence studies were performed on days 2-7 of culture. Both gonadotropins decreased KL mRNA levels as early as 2 h after treatment. The maximal response to hCG and rhFSH treatment was observed at 7-24 h. Concentration-dependence studies performed 8 or 24 h after treatment indicated that the maximal inhibition occurred with 10-100 ng/ml hCG and 100-300 ng/ml rhFSH. We conclude that 1) the KL transcripts encoding 248- and 220-aa transmembrane proteins are expressed in vivo in the human ovary and in cultured human GL cells; and 2) KL transcript levels are rapidly decreased by gonadotropins in a time- and concentration-dependent manner in cultured GL cells. Thus, KL expression is hormonally regulated in human granulosa cells, and this growth factor may control the function of the ovarian follicle during the human menstrual cycle.
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PMID:Expression of c-kit ligand messenger ribonucleic acids in human ovaries and regulation of their steady state levels by gonadotropins in cultured granulosa-luteal cells. 754 3

In the present study we report the isolation and characterization of a clonal Sertoli cell line (42GPA9) from sexually mature polyoma virus large T (PyLT) transgenic mice. The cells multiplied indefinitely and expressed large T antigen. The 42GPA9 cell line expressed biochemical features associated with normal Sertoli cells. Transferrin, sulfated glycoprotein-2, and the ligand of c-kit were detected by reverse transcription-polymerase chain reactions and Western blot analyses. Zymographic analysis indicated that the 42GPA9 cell line secreted tissue-type plasminogen activator. These cells also retained FSH receptors as suggested by their specific responsiveness to the gonadotropin (morphological and phagocytic changes, stimulation of cAMP production) and the detection of FSH receptor mRNAs. Another original aspect of the 42GPA9 cell line is its ability to form tight junctions at confluency as demonstrated by electron microscopic study and immunolocalization of the tight junction-associated protein zonula occludens 1. The 42GPA9 cell line, which has retained several important hallmarks of normal Sertoli cells, may prove useful for further studies on Sertoli cell behavior and on Sertoli-germ cell interactions in the mature testis.
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PMID:Characterization of a clonal Sertoli cell line using adult PyLT transgenic mice. 947 18

In this short overview we summarize recent progress made in some areas of fundamental research related to spermatogenesis and its control. After a brief reminder of the main characteristics of the spermatogenic process we focus on the determinants of sperm output. Particular attention is paid to factors controlling the number of Sertoli cells, to the role of germ cell apoptosis, and to factors rendering human spermatogenesis relatively inefficient. Thereafter, we summarize recent insights on the relative role of testosterone and FSH in the endocrine control of human spermatogenesis. The potential contribution of testosterone metabolites such as 5alpha-dihydrotestosterone and 17beta-estradiol is discussed in the light of novel experimental paradigms. The contribution of cell-cell interactions to spermatogenic control is illustrated on the hand of the kit-ligand-c-kit-receptor system and the scientific and potential therapeutic potential of germ cell transplantation techniques underlined. Finally we focus on clinical and fundamental approaches which contribute to our understanding of specific genes involved in spermatogenesis. It is concluded that research in the field of spermatogenesis is rapidly expanding and that several recent findings will lead to diagnostic and therapeutic applications in the near future.
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PMID:Spermatogenesis and spermatogenic control: a state of the art. 1044 90

Initiation of folliculogenesis through the induction of primordial follicle development in the ovary has an important role in determining the fertility and reproductive fitness of most mammalian species. The factors that control this critical process are largely unknown. The hypothesis tested in the current study was that kit-ligand/stem cell factor (KL) promotes the initiation and progression of primordial follicle development in the ovary. Ovaries from 4-day-old rats were maintained in organ culture for 5 and 14 days and treated with no factor (control), recombinant kit-ligand (KL), or gonadotropins (FSH and hCG). Follicles in ovarian sections were counted and histologically classified as primordial (stage 0), early primary (stage 1), primary (stage 2), transitional (stage 3), or preantral (stage 4). Fresh ovaries from 4-day-old rats contained 68% primordial follicles (stage 0) and 32% developing follicles (stages 1-4) per section. After 5 and 14 days in culture, section from control ovaries contained approximately 41% and 55%, respectively, developing follicles (stage 1-4) per section due to spontaneous development of primordial follicles. Spontaneous primordial follicle development was completely blocked by ACK-2, a c-kit antibody that blocks KL actions. This observation suggests that endogenous KL is necessary for primordial follicle development in vitro. After 14 days of KL treatment, sections from ovaries contained 17% primordial follicles (stage 0) and 83% developing follicles (stage 1-4) per section demonstrating a dramatic induction of primordial follicle development by KL. Gonadotropins (FSH and hCG) did not induce primordial follicle development but did increase the percentage of preantral follicles (stage 4) per section. This small increase in preantral follicles in response to gonadotropins was blocked by ACK-2 suggesting that KL may in part mediate gonadotropin actions after the initiation of primordial follicle development. Ovaries contained an average of 309+/-10 follicles per section. The total number of follicles per section did not significantly vary between treatments suggesting that the effects of KL were not due to an alteration in follicle number (i.e. survival). KL appears to be one of the first factors identified to be involved in the promotion of primordial follicle development. Results suggest that KL is necessary and sufficient to induce primordial follicle development and initiate folliculogenesis.
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PMID:Kit-ligand/stem cell factor induces primordial follicle development and initiates folliculogenesis. 1046

Premature ovarian failure is defined as amenorrhea with hypo-oestrogenism and elevated gonadotrophins occurring before the age of 40 years. In theory, ovarian failure may occur because of a decreased pool of primordial follicles, because ovarian apoptosis is increased or accelerated or because the follicle maturation is interrupted before the preovulatory stage. The mechanisms inducing premature ovarian failure have been described in a few number of cases. Atm or c-kit gene mutations induce a very low pool of primordial follicles. In chromosome X abnormalities, chemotherapy, galactosemia and blepharophimosis syndrome apoptosis is increased. Follicle maturation is interrupted in FSH and LH receptor mutations or in autoimmunity. However, in most cases, the etiology remains idiopathic. A better knowledge in genes involved in ovarian apoptosis should enhance our understanding of premature ovarian failure. Meanwhile, the best treatment is to give hormonal replacement therapy and send the patient to oocyte donation program when they desire to be pregnant.
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PMID:[Premature ovarian insufficiency]. 1048 61

Stem cell factor (SCF) plays an important role in migration, adhesion, proliferation, and survival of primordial germ cells and spermatogonia during testicular development. However, the function of SCF in the adult testis is poorly described. We have previously shown that, in the presence of SCF, there were more type A spermatogonia incorporating thymidine at stage XII of rat seminiferous tubules cultured in vitro than in the absence of SCF, implying that the increased DNA synthesis might result from enhanced survival of spermatogonia. To explore the potential pro-survival function of SCF during spermatogenesis, the seminiferous tubules from stage XII were cultured in the presence or absence of SCF (100 ng/ml) for 8, 24, 48, and 72 hours, respectively, and apoptosis was analyzed by DNA laddering and in situ 3'-end labeling (ISEL) staining. Surprisingly, not only spermatogonia, but also spermatocytes and spermatids, were protected from apoptosis in the presence of SCF. Apoptosis took place much later and was less severe in the SCF-treated tubules than in the controls. Based on previous studies showing that FSH prevents germ cells from undergoing apoptosis in vitro, and that SCF level is increased dramatically in response to FSH stimulation, we also tested if the pro-survival effect of FSH is mediated through SCF by using a function-blocking monoclonal antibody, ACK-2, to block SCF/c-kit interaction. After 24 hours of blockade, the protective effect of FSH was partially abolished, as manifested by DNA laddering and ISEL analyses. The present study demonstrates that SCF acts as an important survival factor for germ cells in the adult rat testis and FSH pro-survival effect on germ cells is mediated partially through the SCF/c-kit pathway.
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PMID:Stem cell factor protects germ cells from apoptosis in vitro. 1059 35

Sertoli cells express functional receptors for FSH, one of the two pituitary hormones that regulate spermatogenesis in mammals. We recently produced genetic mutant (FORKO) mice that lack FSH receptor, in order to examine the effects on testicular function and fertility. Mutant males exhibited weight loss of testis, epididymis, and seminal vesicle as well as low levels of testosterone. Except for reduced seminiferous tubular diameter, no gross changes were apparent upon histological examination. Analysis of testicular germ cells by flow cytometry revealed a significant increase in the percentage of 2C cells (spermatogonia and non-germ cells) and a significant decrease in the percentage of HC cells (elongated spermatids) of FORKO males. The absolute number of homogenization-resistant elongated spermatids was also significantly reduced in the mutant males. A 2-fold increase in c-kit-positive 2C cells was recorded in the mutant males. Elongated spermatids of FORKO males showed a dramatic increase in propidium iodide binding suggesting reduced nuclear compaction. The increase in size of the sperm head in mutants, as well as susceptibility to dithiothreitol-induced decondensation, suggests the inadequate condensation of sperm chromatin. Sperm chromatin structure assay, a technique that reflects DNA stability, revealed that sperm from FORKO males are susceptible to acid denaturation, indicating the poor quality of sperm. These data allow us to conclude that genetic disruption of FSH receptor signaling in the rodent induces major changes that might contribute to reduced fertility.
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PMID:Qualitative and quantitative decline in spermatogenesis of the follicle-stimulating hormone receptor knockout (FORKO) mouse. 1077 61

Bcl-w, a prosurvival member of the Bcl-2 family, is essential for spermatogenesis. However, the mechanisms by which Bcl-w participates in the regulation of apoptosis in the testis are largely unknown. To explore the potential role of Bcl-w in the regulation of apoptosis in the testis, the expression of Bcl-w mRNA and protein during testicular development and spermatogenesis, the dimerization with the proapoptosis members of the Bcl-2 family, and the responses to hormonal stimulation in vitro and apoptosis-inducing signals in vivo were investigated. Both Bcl-w mRNA and protein were detected in Sertoli cells, spermatogonia, and spermatocytes, as well as in Leydig cells. The steady-state levels of Bcl-w mRNA and protein were much higher in Sertoli cells than in spermatogonia and spermatocytes. In the adult rat testis, both Bcl-w mRNA and protein in Sertoli cells displayed a stage-specific expression pattern. Bcl-w could form complexes with Bax and Bak but not with Bad. Bax and Bak were immunohistochemically localized to the same cell types as Bcl-w, but with higher expression levels in spermatocytes and spermatogonia than in Sertoli cells. FSH could up-regulate Bcl-w mRNA levels in the seminiferous tubules cultured in vitro, whereas no effect was observed when testosterone was applied. Three animal models that display spermatogonial apoptosis induced by blockade of stem cell factor/c-kit interaction by a function-blocking anti-c-kit antibody, spermatocyte apoptosis induced by methoxyacetic acid, and apoptosis of spermatogonia, spermatocytes, and spermatids induced by testosterone withdrawal after ethylene dimethane sulfonate treatment were employed to check the changes of Bcl-w, Bax, and Bak protein levels during apoptosis of specific germ cells. In all three models, the ratios of Bax/Bcl-w and Bak/Bcl-w were significantly elevated. The present study suggests that Bcl-w is an important prosurvival factor of Sertoli cells, spermatogonia, and spermatocytes and participates in the regulation of apoptosis by binding proapoptotic factors Bax and Bak. The ratios of Bax/Bcl-w and Bak/Bcl-w may be decisive for the survival of Sertoli cells, spermatogonia, and spermatocytes.
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PMID:Bcl-w forms complexes with Bax and Bak, and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. 1080 32

Although earlier studies focused on the hormonal regulation of antral and preovulatory follicles, recent studies indicate the importance of the hormonal control mechanism for preantral follicles. The endocrine hormone FSH is not only a survival factor for early antral follicles but also a potent growth and differentiation factor for preantral follicles. In addition, KGF secreted by theca cells and c-kit ligand secreted by granulosa cells play paracrine roles in the regulation of preantral follicle growth and development. Furthermore oocyte-derived GDF-9 promotes the growth and differentiation of early follicles by acting on somatic cells in the follicle. It is likely that the genetic makeup of an oocyte could determine the secretion of oocyte hormones which would, in turn, regulate the growth and differentiation of the surrounding somatic cells of that follicle. A better understanding of the hormonal mechanisms underlying early follicle development could provide a refined culture system for the in vitro maturation of fertilizable oocytes and future design of fertility and contraceptive agents.
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PMID:Hormonal regulation of early follicle development in the rat ovary. 1096 80

The tyrosine-kinase receptor c-kit and its ligand, stem cell factor (SCF), are essential for the maintenance of primordial germ cells (PGCs) in both sexes. However, c-kit and a post-meiotic-specific alternative c-kit gene product play important roles also during post-natal stages of spermatogenesis. In the adult testis, the c-kit receptor is re-expressed in differentiating spermatogonia, but not in spermatogonial stem cells, whereas SCF is expressed by Sertoli cells under FSH stimulation. SCF stimulates DNA synthesis in type A spermatogonia cultured in vitro, and injection of anti-c-kit antibodies blocks their proliferation in vivo. A point mutation in the c-kit gene, which impairs SCF-mediated activation of phosphatidylinositol 3-kinase, does not cause any significant reduction in PGCs number during embryonic development, nor in spermatogonial stem cell populations. However males are completely sterile due to a block in the initial stages of spermatogenesis, associated to abolishment of DNA-synthesis in differentiating A1-A4 spermatogonia. With the onset of meiosis c-kit expression ceases, but a truncated c-kit product, tr-kit, is specifically expressed in post-meiotic stages of spermatogenesis, and is accumulated in mature spermatozoa. Microinjection of tr-kit into mouse eggs causes their parthenogenetic activation, suggesting that it might play a role in the final function of the gametes, fertilization.
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PMID:Role of c-kit in mammalian spermatogenesis. 1107 57


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