The Expression Pattern of the c-kit Ligand in Gonads of Mice Supports a Role for the c-kit Receptor in Oocyte Growth and in Proliferation of Spermatogonia

1993 ◽  
Vol 157 (1) ◽  
pp. 85-99 ◽  
Author(s):  
Katia Manova ◽  
Eric J. Huang ◽  
Michael Angeles ◽  
Victor De Leon ◽  
Sandra Sanchez ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Oocyte Growth ◽  
Kit Ligand ◽  
Kit Receptor

The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis

Development ◽  
1993 ◽  
Vol 119 (Supplement) ◽  
pp. 125-137 ◽  
Author(s):  
Peter Besmer ◽  
Katia Manova ◽  
Regina Duttlinger ◽  
Eric J. Huang ◽  
Alan Packer ◽  
...  
Keyword(s):  
Neural Crest ◽  
Germ Cells ◽  
Primordial Germ Cells ◽  
The Body ◽  
Receptor Expression ◽  
Oocyte Growth ◽  
Cellular Targets ◽  
Steel Factor ◽  
Kit Ligand ◽  
Kit Receptor

The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit receptor subfamily. The kit-ligand, KL, also called steel factor, is synthesized from two alter natively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms of KL or can function as cell-associated molecules. The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis. The c-kit receptor is expressed in the cellular targets of W and Sl mutations, while KL is expressed in their microenvironment. In melanogenesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development and in the melanocytes of postnatal animals. In gametogenesis c-kit is expressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of gametogenesis. Many mutant alleles are known at W and Sl loci and their phenotypes vary in the degree of severity in the different cellular targets of the mutations. While many W and Sl alleles severely affect primordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility. Steel Panda (Slpan) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed. In female Slpan/Slpan mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicating a role for c-kit in oocyte growth. W sh is a c-kit expression mutation, which affects mast cells and melanogenesis. While the mast cell defect results from lack of c-kit expression, the pigmentation deficiency appears to stem from ectopic c-kit receptor expression in the somitic dermatome at the time of migration of melanoblasts from the neural crest to the periphery. It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion. The “sash” or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos.

scholarly journals Alterations in ovarian function of mice with reduced amounts of KIT receptor

Reproduction ◽  
2001 ◽  
pp. 229-237 ◽  
Author(s):  
K Reynaud ◽  
R Cortvrindt ◽  
J Smitz ◽  
F Bernex ◽  
JJ Panthier ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Ovarian Function ◽  
Ovarian Follicle ◽  
Mutant Mice ◽  
Wild Type ◽  
Oocyte Growth ◽  
Preantral Follicles ◽  
Kit Ligand ◽  
Kit Receptor

The KIT receptor, present on oocyte and theca cells in ovarian follicles, and its ligand, KIT LIGAND, produced by granulosa cells, are encoded at the Kit gene and the Mgf gene, respectively. Both Kit and Mgf mutations affect oogenesis and folliculogenesis. In this study, the ovarian function of heterozygous mice with a mutation Kit(W-lacZ) was examined. Firstly, the amounts of KIT and KIT LIGAND proteins in the ovaries of mice at different ages were determined. Secondly, in vivo and in vitro folliculogenesis of wild type and heterozygous mice were compared. Western blotting showed that the amounts of both KIT and KIT LIGAND proteins were decreased in mutant mice. Ovarian follicle populations were counted and more type 5a follicles and fewer type 5b (preantral follicles) were present in ovaries from Kit(W-lacZ/+) ovaries. Furthermore, the relationships between oocyte size and follicle size differed between wild type and heterozygous mice. This finding may be a consequence of altered proliferation of granulosa cells or of altered oocyte growth in mutant mice. Other features of folliculogenesis, such as initiation of follicular growth, total follicle population and follicular atresia, were not affected by the mutation. Analysis of in vitro folliculogenesis did not reveal other differences between wild type and mutant mice. It is concluded that the Kit(W-lacZ) mutation affects the expression of KIT and KIT LIGAND proteins, resulting in alterations in granulosa cell proliferation and/or oocyte growth in preantral follicles.

Downregulation of c-kit (Stem Cell Factor Receptor) in Transformed Hematopoietic Precursor Cells by Stroma Cells

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 554-563 ◽  
Author(s):  
Christoph Heberlein ◽  
Jutta Friel ◽  
Christine Laker ◽  
Dorothee von Laer ◽  
Ulla Bergholz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Stem Cell Factor ◽  
Progenitor Cell ◽  
Receptor Expression ◽  
General Mechanism ◽  
Ligand Interaction ◽  
Kit Ligand ◽  
Kit Receptor ◽  
Progenitor Cell Line

Abstract We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.

The Ligand of the c-kit Receptor Promotes Oocyte Growth

1994 ◽  
Vol 161 (1) ◽  
pp. 194-205 ◽  
Author(s):  
Alan I. Packer ◽  
Ying Chang Hsu ◽  
Peter Besmer ◽  
Rosemary F. Bachvarova
Keyword(s):  
Oocyte Growth ◽  
Kit Receptor

scholarly journals An Allelic Series of Mutations in the Kit ligand Gene of Mice. I. Identification of Point Mutations in Seven Ethylnitrosourea-Induced KitlSteel Alleles

Genetics ◽  
2002 ◽  
Vol 162 (1) ◽  
pp. 331-340 ◽  
Author(s):  
S Rajaraman ◽  
W S Davis ◽  
A Mahakali-Zama ◽  
H K Evans ◽  
L B Russell ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Stem Cell Factor ◽  
Genetic Resource ◽  
Point Mutations ◽  
Exon Skipping ◽  
Missense Mutations ◽  
Allelic Series ◽  
Kit Ligand ◽  
Kit Receptor ◽  
Induced Mutants

Abstract An allelic series of mutations is an extremely valuable genetic resource for understanding gene function. Here we describe eight mutant alleles at the Steel (Sl) locus of mice that were induced with N-ethyl-N-nitrosourea (ENU). The product of the Sl locus is Kit ligand (or Kitl; also known as mast cell growth factor, stem cell factor, and Steel factor), which is a member of the helical cytokine superfamily and is the ligand for the Kit receptor tyrosine kinase. Seven of the eight ENU-induced KitlSl alleles, of which five cause missense mutations, one causes a nonsense mutation and exon skipping, and one affects a splice site, were found to contain point mutations in Kitl. Interestingly, each of the five missense mutations affects residues that are within, or very near, conserved α-helical domains of Kitl. These ENU-induced mutants should provide important information on structural requirements for function of Kitl and other helical cytokines.

scholarly journals The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

1992 ◽  
Vol 175 (1) ◽  
pp. 245-255 ◽  
Author(s):  
B K Wershil ◽  
M Tsai ◽  
E N Geissler ◽  
K M Zsebo ◽  
S J Galli
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

The Receptor Protein Tyrosine Phosphatase, PTP-RO, Is Upregulated During Megakaryocyte Differentiation and Is Associated With the c-Kit Receptor

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 539-549 ◽  
Author(s):  
Yoshitaka Taniguchi ◽  
Roanna London ◽  
Karin Schinkmann ◽  
Shuxian Jiang ◽  
Hava Avraham
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tyrosine Kinase Receptor ◽  
Transfected Cells ◽  
Kit Ligand ◽  
Kit Receptor ◽  
Megakaryocytic Cell

Abstract We have recently isolated a cDNA encoding a novel human receptor-type tyrosine phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron), from 5-fluorouracil–treated murine bone marrow cells. PTP-RO is a human homologue of murine PTPλ and is related to the homotypically adhering κ and μ receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the function of PTP-RO in megakaryocytic cells and its potential involvement in the stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP-RO. PTP-RO was found to be associated with the c-Kit receptor in these transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in their proliferative response to the SCF/Kit ligand. In addition, we assessed the association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells. Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway.

The Receptor Protein Tyrosine Phosphatase, PTP-RO, Is Upregulated During Megakaryocyte Differentiation and Is Associated With the c-Kit Receptor

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 539-549
Author(s):  
Yoshitaka Taniguchi ◽  
Roanna London ◽  
Karin Schinkmann ◽  
Shuxian Jiang ◽  
Hava Avraham
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Tyrosine Kinase Receptor ◽  
Transfected Cells ◽  
Kit Ligand ◽  
Kit Receptor ◽  
Megakaryocytic Cell

We have recently isolated a cDNA encoding a novel human receptor-type tyrosine phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron), from 5-fluorouracil–treated murine bone marrow cells. PTP-RO is a human homologue of murine PTPλ and is related to the homotypically adhering κ and μ receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the function of PTP-RO in megakaryocytic cells and its potential involvement in the stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP-RO. PTP-RO was found to be associated with the c-Kit receptor in these transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in their proliferative response to the SCF/Kit ligand. In addition, we assessed the association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells. Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway.

Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive

2014 ◽  
Vol 28 (10) ◽  
pp. 4441-4456 ◽  
Author(s):  
Séverine Tabone‐Eglinger ◽  
Zuleika Calderin‐Sollet ◽  
Perrine Pinon ◽  
Nicole Aebischer ◽  
Monique Wehrle‐Haller ◽  
...  
Keyword(s):  
Kit Ligand ◽  
Kit Receptor ◽  
Membrane Bound

Additive effect of mouse genetic background and mutation ofMITF gene on decrease of skin mast cells

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1344-1350 ◽  
Author(s):  
Eiichi Morii ◽  
Keisuke Oboki ◽  
Tomoko Jippo ◽  
Yukihiko Kitamura
Keyword(s):  
Transcription Factor ◽  
Mast Cells ◽  
Receptor Tyrosine Kinase ◽  
Genetic Background ◽  
Leucine Zipper ◽  
Basic Helix Loop Helix ◽  
Kit Ligand ◽  
Helix Loop Helix ◽  
Kit Receptor ◽  
Mouse Genetic

The mi transcription factor (MITF) is a basic-helix-loop-helix leucine zipper transcription factor and is encoded by mi locus. The mi/mi mutant mice showed a significant decrease of skin mast cells in C57BL/6 (B6) genetic background but not in WB genetic background. Kit ligand (KitL) is the most important growth factor for development of mast cells, and the decrease of skin mast cells in B6-mi/mi mice was attributable to the reduced expression of c-kit receptor tyrosine kinase (KIT) that is a receptor for KitL. However, the expression level of KIT in WB-mi/mi mast cells was comparable with that of B6-mi/mi mast cells, suggesting that a factor compensating the reduced expression of KIT was present in WB-mi/mi mice. By linkage analysis, such a factor was mapped on chromosome 10. The mapped position was closely located to the KitL locus. Two alternative spliced forms are known in KitL mRNA: KL-1 and KL-2. Soluble KitL, which is important for development of skin mast cells, is produced more efficiently from KL-1 mRNA than from KL-2 mRNA. The KL-1/KL-2 ratio was higher in WB-mi/mi than in B6-mi/mi mice, suggesting that the larger amount of soluble KitL may compensate for the reduced expression of KIT in WB-mi/mi mice.

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