Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primordial germ cells (PGCs) undergo proliferation, invasion, guided migration, and aggregation to form the gonad. Here we show that in Drosophila, the receptor tyrosine kinase Torso activates both STAT and Ras during the early phase of PGC development, and coactivation of STAT and Ras is required for PGC proliferation and invasive migration. Embryos mutant for stat92E or Ras1 have fewer PGCs, and these cells migrate slowly, errantly, and fail to coalesce. Conversely, overactivation of these molecules causes supernumerary PGCs, their premature transit through the gut epithelium, and ectopic colonization. A requirement for RTK in Drosophila PGC development is analogous to the mouse, in which the RTK c-kit is required, suggesting a conserved molecular mechanism governing PGC behavior in flies and mammals.
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PMID:Coactivation of STAT and Ras is required for germ cell proliferation and invasive migration in Drosophila. 1460 78

We have used the parasite helminth Trichinella spiralis to study the generation and differentiation of mast cell progenitors in the bone marrow of mice, as this infection triggers an intestinal mastocytosis which correlates with parasite expulsion. C-kit+ mast cell progenitors have previously been defined by methylcellulose colony-forming units and by limiting dilution assays in vitro. In vivo experiments have demonstrated the essential requirement by mast cells for specific integrin expression. We have defined 2 c-kit+ populations in the bone marrow, one of which coexpresses CD49d/beta7 integrin, a marker essential for small intestine immigration. We have confirmed the phenotype of these cells by using antagonistic anti-c-kit antibody in vivo. Our data show that the loss of c-kit+/beta7+ cells from the bone marrow correlates with their appearance in the blood and precedes detection of mature mast cells in the gut by 3 days. This exit correlates with an increase in soluble stem cell factor (SCF) in the serum, suggesting that the c-kit/SCF interaction may be chemotactic or haptotactic in nature. This study shows that during infection the bone marrow environment generates mast cells destined for the intestinal mucosa before their exit into the periphery, indicating a clear interplay between infection site and hematopoietic tissue.
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PMID:In vivo exit of c-kit+/CD49d(hi)/beta7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis. 1460 54

Interstitial cells of Cajal (ICC) are involved in the generation of electrical rhythmicity of intestinal muscle and in the transduction of neural inputs in the gut. Although the expression of receptors for neurotransmitters and hormones and some second messengers have been investigated in ICC, the protein kinases present in these cells have not been well documented. This study has demonstrated the immunohistochemical localisation of PKA, PKC gamma and PKC theta in ICC that were identified by the known ICC marker, c-Kit, in the guinea-pig gut. Other PKCs, PKC alpha, beta, delta, epsilon, eta, iota and lambda, and Ca(2+)-calmodulin-dependent protein kinase II were not localised in ICC. Double labelling studies were conducted on longitudinal muscle-myenteric plexus and external muscle-myenteric plexus preparations of the oesophagus, stomach (fundus, corpus and antrum), duodenum, distal ileum, caecum, proximal and distal colon, and rectum. The three protein kinases were detected in c-Kit-immunoreactive ICC at the level of the myenteric plexus (IC-MY), in the muscle (IC-IM) and at the level of the deep muscular plexus (IC-DMP) in the small intestine. PKA was found in over 90% of IC-IM in all regions examined, and in over 90% of IC-MY in the gastric body and antrum and throughout the small and large intestines. PKC gamma was in the majority of ICC in the gastric body and antrum and in the small intestine, but was largely absent from ICC in the oesophagus, proximal stomach and large intestine. PKC theta occurred in the majority of ICC in all regions except the rectum. The intensity of staining was greatest for PKA, with PKC gamma giving comparatively weak labelling of ICC. PKA was also detected in myenteric neurons, smooth muscle, macrophages and fibroblast-like cells. PKC gamma labelling occurred in large, multipolar neurons throughout the small and large intestine, as well as in lymph vessels and in capillaries. It is concluded that PKA, PKC gamma and PKC theta are all present in ICC, with the differences in their localisations suggesting specific roles for each in ICC function.
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PMID:Protein kinases expressed by interstitial cells of Cajal. 1465 70

The understanding of mesenchymal neoplasms of the gastrointestinal tract has evolved dramatically over the last two decades since gastrointestinal stromal tumor (GIST) was described as the most common stromal tumor arising anywhere from the esophagus to the ano-rectum. Although morphologically similar to other benign and malignant smooth muscle and neural stromal neoplasms, GIST constitutes a distinct group of rare gastrointestinal tract tumors that originate from the interstitial cells of Cajal, regulators of gut peristalsis that normally express CD117, which is the product of the c-KIT proto-oncogene that encodes a tyrosine kinase receptor that regulates cellular proliferation in GISTs. Virtually all GISTs occur from mutations of the c-KIT oncogene and exhibit consistent expression of c-KIT (CD117), which is considered the most specific criterion for a diagnosis of GIST. Gastrointestinal stromal tumors vary in their behavior and several features have to be considered to assess their malignant potential. The advent of sophisticated imaging techniques for the evaluation and sampling of stromal tumors of the gastrointestinal tract has resulted in improved detection of GISTs. The identification of a novel tumor-specific target in c-KIT resulted in the development of a tyrosine kinase-inhibitor (imatinib mesylate) that provides an encouraging option for treating GISTs. This article reviews recent advances in the understanding of the cell biology, diagnosis, and therapy of GISTS.
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PMID:Recent advances in cell biology, diagnosis, and therapy of gastrointestinal stromal tumor (GIST). 1472 14

Using an embryoid body (EB) culture system, we have made a functional organlike cluster: the "gut" from embryonic stem (ES) cells (ES gut). There are many types of ES clusters, because ES cells have a pluripotent ability to develop into a wide range of cell types. Before inducing specific differentiation by exogenously added factors, we characterized comprehensive physiological and morphological properties of ES guts. Each ES gut has a hemispherical (or cystic) structure and exhibits spontaneous contractions [mean frequency: 13.5 +/- 8.8 cycles per min (cpm)]. A dense distribution of interstitial cells of Cajal (ICC) was identified by c-Kit immunoreactivity, and specific subcellular structures of ICC and smooth muscle cells were identified with electron microscopy. ICC frequently formed close contacts with the neighboring smooth muscle cells and occasionally formed gap junctions with other ICC. Widely propagating intracellular Ca(2+) concentration oscillations were generated in the ES gut from the aggregates of c-Kit immunopositive cells. Plateau potentials, possibly pacemaker potentials in ICC, and electrical slow waves were recorded for the first time. These events were nifedipine insensitive, as in the mouse gut. Our present results indicate that the rhythmic pacemaker activity generated in ICC efficiently spreads to smooth muscle cells and drives spontaneous rhythmic contractions of the ES gut. The present characterization of physiological and morphological properties of ES gut paves the way for making appropriate models to investigate the origin of rhythmicity in the gut.
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PMID:Characterization of in vitro gutlike organ formed from mouse embryonic stem cells. 1496 Apr 14

In this study, we performed a detailed topographical study on the development of ganglion plexuses and the smooth muscle layers of human embryonic and fetal gut. Neuron and glia differentiation was investigated with anti-PGP9.5 and anti-S100 antibodies respectively. The differentiation of smooth muscle and interstitial cells of Cajal (ICC) was studied with anti-smooth muscle alpha-actin and anti-C-Kit antibodies respectively. By week 7, rostro-caudal neural crest cell (NCC) colonization of the gut was complete, and NCCs have differentiated into neurons and glia. At the foregut, neurons and glia were aggregated into ganglion plexus in the myenteric region, and the longitudinal and circular muscle layers have started to differentiate; however, neurons and glia were not found in the submucosa. At the hindgut, neurons and glia were dispersed within the mesenchyme. Myenteric plexus, longitudinal and circular muscle layers formed along the entire gut by week 9. Scattered and individual neurons and glia, and small ganglion plexuses were detected in the foregut and midgut submucosa by week 12. Ganglion plexus was not seen in the hindgut submucosa until week 14. Muscularis mucosae was formed at the foregut and midgut by week 12 but was only discernible at the hindgut 2 weeks later. As the gut wall developed, ganglion plexus increased in size with more neurons and glia, and the formation of intra-plexus nerve fascicle. ICCs were localized in the ganglion plexus as early as week 7. ICCs were initially dispersed in the plexus and were preferentially localized at the periphery of the plexus by week 20. The specification of the annular layers of human embryonic and fetal gut follows a strict spatio-temporal pattern in a rostro-caudal and centripetal manner suggesting that interaction between (1) homotypic and/or heterotypic cells; and (2) cells and the extracellular matrix is critical for the embryonic development of the gut mesenchyme and the enteric nervous system.
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PMID:Embryonic development of the ganglion plexuses and the concentric layer structure of human gut: a topographical study. 1499 1

Intracellular Ca(2+) ([Ca(2+)](i)) oscillations seen in interstitial cells of Cajal (ICCs) are considered to be the primary pacemaker activity in the gut. Here, we show evidence that periodic Ca(2+) release from intracellular Ca(2+) stores produces [Ca(2+)](i) oscillations in ICCs, using cell cluster preparations isolated from mouse ileum. The pacemaker [Ca(2+)](i) oscillations in ICCs are preserved in the presence of dihydropyridine Ca(2+) antagonists, which suppress Ca(2+) activity in smooth muscle cells. However, applications of drugs affecting either ryanodine receptors or inositol 1,4,5-trisphosphate receptors terminated [Ca(2+)](i) oscillations at relatively low concentrations. RT-PCR analyses revealed a predominant expression of type 3 RyR (RyR3) in isolated c-Kit-immunopositive cells (ICCs). Furthermore, we demonstrate that pacemaker-like global [Ca(2+)](i) oscillation activity is endowed by introducing RyR3 into HEK293 cells, which originally express only IP(3)Rs. The reconstituted [Ca(2+)](i) oscillations in HEK293 cells possess essentially the same pharmacological characteristics as seen in ICCs. The results support the functional role of RyR3 in ICCs.
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PMID:Requirement of ryanodine receptors for pacemaker Ca2+ activity in ICC and HEK293 cells. 1516 38

It is postulated that the electric waves of the gut are generated by interstitial cells of Cajal (ICC). We hypothesized the presence of ICC in the rectum as initiating the rectal electric activity. The current study investigated this hypothesis. Two rectal specimens were taken from healthy areas of excised rectum of 22 rectal cancer patients (age 44.6+/-.2 SD years, 12 men, 10 women). The study specimens were subjected to c-kit immunohistochemistry. Controls for antisera specificity consisted of tissue incubation with normal rabbit serum substituted for the primary antiserum. C-kit positive branched ICC-like cells were detected in the rectal musculature of the studied specimens. They were distinguishable from the c-kit-negative non-branched smooth muscle cells and from the c-kit positive but non-branched mast cells. Immunoreactivity was absent in the negative controls. We have identified in the rectum for the first time cells with morphologic and immunologic phenotypes similar to the ICC of the gut. The role of these cells in normal physiologic and pathologic conditions of the rectum needs further studies.
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PMID:Identification of interstitial cells of Cajal in the human rectum. 1535 19

Intestinal motility disorders are a major cause of morbidity after surgical repair of intestinal atresia of unknown mechanism. We hypothesized that interruption of antenatal peristalsis may disturb the normal development of the enteric nervous system. Using a series of neuronal (synaptophysin, neuronal nitric oxide synthase, neurofilaments) and nonneuronal markers (glial acidic fibrillary protein and c-Kit) and immunohistochemistry, we have defined developmental steps of the enteric nervous system in normal intestine (12 fetuses, 15 children, and 4 adults) and their alterations above and below the obstacle in 22 human intestinal atresia compared with age-matched controls. Antisynaptophysin antibody revealed the progressive conversion of the myenteric plexus from a continuous belt into regularly spaced ganglions during normal fetal gut development and, by contrast, the significantly delayed appearance of individual neuronal ganglions in the distal segments of atresia (p < 0.05). Staging using three other markers for neuronal (neurofilaments and neuronal nitric oxide synthase) and nonneuronal cells (glial acidic fibrillary protein) confirmed that maturation of the myenteric plexus was significantly delayed below atresia (p < 0.01). These results indicate that intestinal atresia impairs the development of the enteric nervous system and provide an anatomical substrate for the motility disorders observed after surgical repair. They point to the role of peristalsis in normal gut development and suggest that stimulation of peristalsis might be used to accelerate recovery.
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PMID:Fetal intestinal obstruction induces alteration of enteric nervous system development in human intestinal atresia. 1549 9

The interstitial cells of Cajal (ICC) play an important role in the control of gut motility. The recognition that the ICC cell membrane harbors the c-kit receptor (CD117) sparked rapid advancement in ICC research on the gut and certain pathologies using immunochemical and molecular methods. The question arises whether ICC exist in the upper urinary tract (UUT) and trigger motility. The present study analyzed the distribution of the c-kit receptor in the normal human UUT compared with various species. Immunohistochemistry (alkaline-phosphatase-anti-alkaline-phosphatase technique, immunofluorescence) was applied on serial sections using monoclonal and polyclonal antibodies recognizing the c-kit receptor. C-kit staining was compared with standard endothelial, epithelial, neurogenic, histiocytic, mast cell, and smooth muscle markers, as well as a negative control. Normal proximal, middle, and distal ureter segments were analyzed in rodents, carnivores, porcines, cow, and humans. In all species the c-kit receptor was detected in either round or spindle-shaped cells. Because of their antigenic profile, the round cells were identified as mast cells occurring in all layers of the ureteral wall except the urothelium and were more frequent in humans. In contrast, the population of spindle-shaped cells was marked only by anti-c-kit receptor antibodies, thus resembling ICC. These ICC-like cells were found among the inner and outer smooth muscle layers and in the lamina propria of all species. In humans, spindle-shaped cells were also found vertically oriented within the urothelium. Our morphological data present for the first time the distribution of ICC in the UUT of various species. The ubiquitous distribution in the entire pyeloureteral complex provides strong evidence that ICC generate electrical pacemaker activity within the UUT as an intrinsic system. Animal studies may help to understand the physiological importance of these ICC-like cells. The significance of these findings needs to be evaluated by functional studies and investigations of certain congenital pathologies with disturbance of the urinary outflow.
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PMID:Cajal-like cells in the upper urinary tract: comparative study in various species. 1565 10


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