| KIT proto-oncogene receptor tyrosine kinase | OKDB#: 160 |
| Symbols: | KIT | Species: | human | ||
| Synonyms: | PBT, SCFR, C-Kit, CD117 | Locus: | 4q12 in Homo sapiens | HPMR |
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| General Comment |
Fertility: the role of mTOR signaling and KIT ligand. Hsueh AJ et al. Activation of a limited pool of diminishing ovarian follicles determines women's reproductive lifespan. A recent rodent study describes the role of mTOR signaling and KIT ligand in granulosa cells of primordial follicles for follicle activation and for reproductive lifespan regulation.
The protooncogene KIT encodes a transmembrane tyrosine kinase. Geissler et al. (1988) showed that in the mouse the kit gene is disrupted in 2 spontaneous mutant W alleles. The provirus of the Hardy-Zuckerman 4 feline sarcoma virus was molecularly cloned. A segment from the middle of the provirus, showing homology to mammalian genomic DNA, was termed v-kit. Yarden et al. (1987) assigned the KIT locus to 4cen-q21. They demonstrated that the homologous gene is on chromosome 5 in the mouse.
NCBI Summary: This gene encodes the human homolog of the proto-oncogene c-kit. C-kit was first identified as the cellular homolog of the feline sarcoma viral oncogene v-kit. This protein is a type 3 transmembrane receptor for MGF (mast cell growth factor, also known as stem cell factor). Mutations in this gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myelogenous lukemia, and piebaldism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008] |
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| General function | Receptor, Cell death/survival, Oncogenesis | ||||
| Comment |
The receptor encoded by the W (c-kit) locus is expressed on the membrane of mouse primordial germ cells, whereas stem cell factor (SCF), encoded by the Sl (Steel) locus, is expressed on the membrane of somatic cells associated with both the primordial germ cell migratory pathways and homing sites. Using an in vitro short time assay which allows a quantitative measure of adhesion between cells it was shown, that SCF/c-kit interaction can modulate primordial germ cell adhesion to somatic cells (Pesce et al., 1997).
Both c-kit and steel are contiguously expressed in a wide variety of anatomical locations in both the developing embryo and in the adult. In adult gonads, steel is expressed in the follicular cells of the ovary and in Sertoli cells of the testis, the layers that immediately surround the c-kit expressing germ cells (Motro et al., 1991). |
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| Cellular localization | Plasma membrane | ||||
| Comment | |||||
| Ovarian function |
Follicle endowment, Follicle development, Initiation of primordial follicle growth, Primary follicle growth, Germ cell development, Germ cell migration, Oocyte growth
, First polar body extrusion |
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| Comment | Fertility: the role of mTOR signaling and KIT ligand. Hsueh AJ et al. Activation of a limited pool of diminishing ovarian follicles determines women's reproductive lifespan. A recent rodent study describes the role of mTOR signaling and KIT ligand in granulosa cells of primordial follicles for follicle activation and for reproductive lifespan regulation. /////////// KIT signaling regulates primordial follicle formation in the neonatal mouse ovary. Jones RL 2013 et al. The pool of primordial follicles determines the reproductive lifespan of the mammalian female, and its establishment is highly dependent upon proper oocyte cyst breakdown and regulation of germ cell numbers. The mechanisms controlling these processes remain a mystery. We hypothesized that KIT signaling might play a role in perinatal oocyte cyst breakdown, determination of oocyte numbers and the assembly of primordial follicles. We began by examining the expression of both KIT and KIT ligand in fetal and neonatal ovaries. KIT was expressed only in oocytes during cyst breakdown, but KIT ligand was present in both oocytes and somatic cells as primordial follicles formed. To test whether KIT signaling plays a role in cyst breakdown and primordial follicle formation, we used ovary organ culture to inhibit and activate KIT signaling during the time when these processes occur in the ovary. We found that when KIT was inhibited, there was a reduction in cyst breakdown and an increase in oocyte numbers. Subsequent studies using TUNEL analysis showed that when KIT was inhibited, cell death was reduced. Conversely, when KIT was activated, cyst breakdown was promoted and oocyte numbers decreased. Using Western blotting, we found increased levels of phosphorylated MAP Kinase when KIT ligand was added to culture. Taken together, these results demonstrate a role for KIT signaling in perinatal oocyte cyst breakdown that may be mediated by MAP Kinase downstream of KIT. ///////////////////////// DNA methyltransferase loading, but not de novo methylation, is an oocyte-autonomous process stimulated by SCF signalling. Lees-Murdock DJ et al. Epigenetic reprogramming occurs during oocyte growth in mice, a stage where a number of important events are occurring, including transcription of maternal mRNAs for storage in the mature egg, global transcriptional silencing and the acquisition of meiotic competence. Oocyte growth occurs in conjunction with follicular development over a period of many days. The signals involved in initiating different stages in oocyte and follicular development and the concurrent epigenetic changes are poorly understood. Here we examine the role of stem cell factor (SCF or Kit ligand) on the early- to mid-stages of oocyte growth and on DNA methyltransferase expression and function using a one-step in vitro culture system. Our results show that SCF promotes early oocyte growth and development to the multilaminar follicle stage. Oocyte growth is sufficient to trigger transcription of Dnmt1 and Dnmt3L from dedicated oocyte promoters, and we show that eggs undergoing growth in the absence of follicle development in Foxo3 mutants show elevated levels of Dnmt1. The methyltransferase proteins undergo sequential relocalisation in the oocyte, with DNMT1 being exported from the nucleus at the bilaminar follicle stage, while DNMT3A is transported into the nucleus at the multilaminar stage, indicating an important role for trafficking in controlling imprinting. SCF is thought to signal partly through the phophostidylinositol 3 (PI3) kinase pathway: inhibiting this path was previously shown to prevent FOXO3 nuclear export and we could show here that it also prevented DNMT1 export. Some oocytes reached full size (70 microM) in this in vitro system, but no secondary follicles were formed, most likely due to failure of the thecal layer to form properly. De novo methylation of imprinted genes was seen in some oocyte cultures, with methylation levels being highest for Snrpn and Igf2r which are methylated early in vivo, while Peg1, which is methylated late, showed little or no methylation. SCF treatment did not increase the number of cultures showing methylation. We saw no evidence for de novo methylation of IAP repeats in our cultures. These results suggest that while methyltransferase loading is triggered by oocyte growth, in which SCF plays an important role, complete methylation probably requires progression to the secondary follicle stage and is unlikely to be affected by SCF. Kit Ligand and the Somatostatin Receptor Antagonist, BIM-23627, Stimulate in Vitro Resting Follicle Growth in the Neonatal Mouse Ovary. Gougeon A et al. In the mammalian ovary, kit ligand (KL), coded by a cAMP-stimulatable gene, is a protein that promotes initiation of follicle growth. The neuropeptide somatostatin (SST) is a small peptide that inhibits cAMP generation in many cell types. Consequently, SST receptor agonists might alter KL production and subsequent follicle growth. The present study was undertaken to look for the existence of a functional SST system in the mouse ovary, to test the effects of the SST receptor 2 (SSTR-2) antagonist BIM-23627 on in vitro folliculogenesis, and to compare them with those of KL, which was demonstrated to stimulate follicle growth in the neonatal rat ovary. Pairs of ovaries from 5-d-old mice were incubated in vitro during 15 d in the presence of either KL or BIM-23627. For every mouse, one ovary was cultured in culture medium (control), and the other ovary was cultured in the presence of either KL or BIM-23627. After 5, 10, and 15 d culture, the ovaries were histologically assessed for the content of primordial, primary, and secondary follicles. The SSTR-2 and -5, but not SST, were identified at the transcriptional and translational (mainly in granulosa cells) levels. Both KL and BIM-23627 triggered a reduction of the percentages of primordial follicles and an increase of the percentages of primary and secondary follicles when compared with control ovaries from the same animal. In conclusion, extraovarian SST, acting through its receptors 2 and 5 present on granulosa cells, may be involved in mouse folliculogenesis by reducing recruitment of resting follicles. Yoshida et al. (1997) used ACK2 (c-kit antibody) to indicate the stepwise requirement of c-kit and its ligand in the development of ovarian follicles. Ovarian follicle growth in mice is dependent on c-kit during the first 5 days after birth when the functional FSH receptor is not yet expressed in mouse ovary. A blockade of c-kit function by ACK2 disturbed the onset of primordial follicle development, primary follicle growth, follicular fluid formation of preantral follicles, and penultimate-stage ovarian follicle maturation before ovulation. In contrast, primordial follicle formation and survival, small preantral or antral follicle development, ovulation, and luteinization of the ovulated follicle were not affected by this antibody. Another study by Parrot and Skinner (1999) showed that spontaneous primordial follicle development was completely blocked by ACK2. A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: its role in regulating granulosa cell mitosis Otsuka F, . Although the existence of a regulatory paracrine feedback system between oocytes and follicular somatic cells has been postulated for some time, there has not yet been any definitive evidence that such a communication system exists. Herein we present a previously undescribed oocyte-granulosa cell (GC) feedback communication system involving an oocyte-derived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both of which have been shown to be crucial regulators of female reproduction. We used a coculture system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative feedback loop. Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presence of oocytes. Because c-kit (KL receptor) is expressed in oocytes but not GCs, the oocytes must be involved in mediating the KL-induced GC mitosis. Furthermore, the blockage of c-kit signaling in oocytes by using a c-kit neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte must play a role in the GC responses to BMP-15. In contrast, the c-kit antibody had no effect on the mitotic activities of two other known GC mitogens, activin-A and BMP-7. Altogether, this study presents direct evidence of a negative feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte-GC communication system. We hypothesize that the negative feedback system most likely plays a pivotal role in early folliculogenesis. Kit ligand and c-Kit are expressed during early human ovarian follicular development and their interaction is required for the survival of follicles in long-term culture. Carlsson IB et al. The receptor tyrosine c-Kit and its cognate ligand, c-Kit ligand (KL, stem cell factor, SCF), are involved in ovarian follicular development in several animal species. We studied the expression of KL and c-Kit using in situ hybridization and immunohistochemistry in donated human ovarian cortical tissue. The KL transcripts were expressed in granulosa cells of primary follicles, whereas the expression of c-Kit was confined to the oocyte and granulosa cells in primary and secondary follicles. We employed an ovarian organ culture using firstly serum-containing and then serum-free medium to study the effects of KL and an anti-c-Kit antibody, ACK2, on the development and survival of ovarian follicles in vitro. Culture of ovarian cortical slices for 7 days resulted in a 37% increase in the number of primary follicles and a 6% increase in secondary follicles. The proportion of viable follicles decreased in all cultures. The addition of KL (1, 10 and 100 ng/ml) into the culture media did not affect the developmental stages of the follicles or the proportion of atretic follicles. Inclusion of ACK2 (800 ng/ml) in the culture medium significantly increased the proportion of atretic follicles on days 7 (49 vs 28% in control cultures) and 14 (62 vs 38%) of culture. In conclusion, c-Kit and KL are expressed in human ovaries during follicular development. Blocking the c-Kit receptor induces follicular atresia. The KL/c-Kit signaling system is likely to control the survival of human ovarian follicles during early follicular development. | ||||
| Expression regulated by | LH, Growth Factors/ cytokines | ||||
| Comment | The cyclic secretion of luteinizing hormone results in decreased levels of c-kit transcripts in stromal-derived cells (Motro and Bernstein, 1993).///////Effects of Recombinant Human AMH on SCF Expression in Human Granulosa Cells. Hu R et al. The aim of the present study was to investigate the effects of recombinant human anti-mullerian hormone (rhAMH) on Stem Cell Factor (SCF) expression in human granulosa cells (GCs). GCs were obtained from infertile patients undergoing IVF-ET cycles and cultured with 20?ng/ml of rhAMH. The levels of SCF mRNA and protein were detected in both matched and experimental group by real-time PCR, immunofluorescence, and ELISA, respectively, on day 4 of culture. We found that human GCs expressed SCF mRNA and protein, and SCF expression in the experimental group was significantly lower than that in the matched group (p? | ||||
| Ovarian localization | Primordial Germ Cell, Oocyte, Granulosa, Theca, Surface epithelium, Ovarian tumor | ||||
| Comment |
Expression of KIT in the ovary, and the role of somatic precursor cells. Merkwitz C et al. KIT is a type III receptor protein tyrosine kinase, and KITL its cognate ligand. KIT can mediate its effects via several intracellular signalling pathways, or by formation of a cell-cell anchor with its ligand. Through these mechanisms, KIT controls fundamental cellular processes, including migration, proliferation, differentiation and survival. These cellular processes are modulated by soluble KIT, a cleavage product of KIT, generated at the cell membrane. A cell-retained KIT cleavage fragment also arises from this cleavage event. This cleavage fragment must be distinguished from truncated KIT (trKIT), which originates through cryptic promoter usage. The expression of trKIT is highly restricted to postmeiotic germ cells in the testis. In contrast, KIT, together with its cleavage products, is present in somatic cells and germ cells in the gonads of both sexes. A functional KITL/KIT system is mandatory for normal population of the gonads by germ cells. Signalling via the KITL/KIT system promotes the growth, maturation, and survival of germ cells within the gonads, and prevents meiotic entry and progression. In addition to its importance in germ cell biology, the KITL/KIT system is crucial for gonadal stromal differentiation. During foetal life, KIT is expressed by testicular stromal precursor cells, which develop into Leydig cells. In the ovary, stromal cell KIT expression accompanies theca layer development around advanced follicles. After ovulation, KIT-immunopositive cells translocate from the theca layer to the luteal ganulosa where they contribute to a delicate cellular network that extends between the fully luteinised large luteal cells. In the outer regions of the developing corpus luteum, a highly conspicuous subpopulation of KIT/CD14-double-immunopositive cells can be observed. KIT/CD14-double-immunopositive cells are also seen in the haematopoietic-like colonies of long-term granulosa cultures established from late antral follicles. These cultures demonstrate expression of pluripotency marker genes such as octamer binding transcription factor-3/4 and sex determining region Y-box 2. The KIT/CD14-double-immunopositive cells can be purified and enriched by KIT-immunopositive magnetic cell sorting. Subsequent exposure of the KIT-expressing cells to the hanging drop culture method, combined with haematopoietic differentiation medium, provides the signals necessary for their differentiation into endothelial and steroidogenic cells. This suggests that monocyte-derived multipotent cells are involved in ovarian tissue remodelling. In summary, multicelluar KITL/KIT signalling organizes the stroma in the ovary and testis; monocyte-derived multipotent cells may be involved.
Expression of c-kit mRNA was detected by RT-PCR in human oocytes and granulosa cells. Western blot analysis showed the presence of soluble c-kit protein in the follicular fluid, and lower levels of c-kit protein were detected in the granulosa cells and the supernatant of granulosa cell cultures (Tanikawa et al., 1998).
Through RT-PCR analysis it was shown that c-kit receptor is expressed in theca cells (Parrot and Skinner 1997). Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: New roles for an old timer. Liu K et al. A large amount of information has accumulated over the past decade on how gonadotropins, steroid hormones and growth factors regulate development of the mammalian ovarian follicle. Moreover, the bi-directional communication between mammalian oocytes and their surrounding somatic (granulosa) cells has also been shown to be crucial for this process. The intra-ovarian factors, or more specifically, the intra-oocyte signaling pathways that control oocyte growth and early follicular development are largely unknown, however. Based on both in vitro studies and in vivo functional studies using gene-modified mouse models, this review focuses on the key features of the phosphatidylinositol 3 kinase (PI3K) pathway in growing mouse oocytes and on the novel functions of the oocyte PI3K pathway in controlling mammalian oocyte growth and follicular development that have come to light only recently. We propose that the PI3K pathway in the oocyte, which is activated by granulosa cell-produced Kit ligand (KL) via the oocyte-surface receptor Kit, may serve as an intra-oocyte network that regulates both oocyte growth and the early development of ovarian follicles. |
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| Follicle stages | Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | c-Kit protein was detected in murine ovaries after the time of birth, but not before. The expression of c-kit was observed mainly on the surface of oocytes, but not in granulosa cells nor in interstitial regions. Oocytes of primordial to fully grown Graafian follicles showed the c-kit protein. When ovulation was induced by hCG, the expression of c-kit in ovulated unfertilized oocytes was weaker than in oocytes of Graafian follicles. In summary, the highest expression of c-kit was observed on the surface of oocytes arrested in the diplotene stage of meiotic prophase. With ovulation and the resumption of meiotic maturation, its expression declined (Horie et al., 1991 and Manova et al., 1990). In ovine, c-kit was expressed in a cell-specific manner throughout the corpus luteum (Gentry et al., 1998). | ||||
| Phenotypes | |||||
| Mutations |
4 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Oct. 1, 1999, midnight | by: |
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| last update: | Aug. 9, 2016, 12:42 p.m. | by: | hsueh email: |
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