Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enteric nervous system (ENS) in vertebrates is derived from the neural crest and constitutes the most complex part of the peripheral nervous system. Natural and induced mutagenesis in mammals has shown that the tyrosine kinase receptor RET and its functional ligand glial cell line-derived neurotrophic factor (GDNF) play key roles in the development of the ENS in humans and mice. We have developed and briefly describe here a number of assays that analyze the specific function of the RET receptor and its ligand. Our data suggest that the RET signal transduction pathway has multiple roles in the development of the mammalian ENS.
 ...
PMID:III. Role Of the RET signal transduction pathway in development of the mammalian enteric nervous system. 968 43

Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.
 ...
PMID:Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. 970 Feb

Neurturin (NTN) and glial cell line-derived neurotrophic factor (GDNF) are the first two members of the GDNF family (GF) of neurotrophic factors. These two proteins are potent survival factors for several populations of central and peripheral neurons in mature and developing rodents. The receptor for these factors is a multicomponent complex that includes the RET (rearranged during transfection) tyrosine kinase receptor and one of two glycosyl phosphatidylinositol (GPI)-linked ligand-binding components called GDNF family receptor alphas (GFRalpha-1 and GFRalpha-2). We have used in situ hybridization to study the mRNA expression of NTN, GDNF, RET, GFRalpha-1, and GFRalpha-2 in the central nervous system (CNS) of adult mice. GF receptors are expressed in several areas in which neuronal populations known to respond to NTN and GDNF are located, including the ventral horn of the spinal cord and the compacta region of the substantia nigra. In addition, we have demonstrated receptor expression in other areas of the brain including the thalamus and hypothalamus. Neurons in these areas express GF receptors, and therefore, may respond to NTN or GDNF. NTN and GDNF are expressed in targets of neurons that express GF receptors. The pattern of GF factor and receptor expression in the adult brain suggests a role for these factors in maintaining neuronal circuits in the mature CNS.
 ...
PMID:Expression of neurturin, GDNF, and their receptors in the adult mouse CNS. 970 32

In 1967, Okamoto et al suggested that the absence of ganglion cells in Hirschsprung's disease (HD) was attributable to failure of migration of neural crest cells. The earlier the arrest of migration, the longer the aganglionic segment. Since then, this hypothesis generally has been accepted. However, subsequent experiments using mouse models of intestinal aganglionosis indicate that nerve cells may reach the correct position but then fail to develop or survive. An alternative hypothesis has been proposed that the aganglionosis may be caused by failure of differentiation as a result of microenvironmental changes after the migration has occurred. Extracellular matrix proteins are recognized as important microenvironmental factors. It has been shown that enteric neurogenesis is dependent on extracellular matrices, which provide a migration pathway for neural crest-derived cells and promote the maturation of settled neural crest-derived cells. Altered distributions of extracellular matrices have been shown in human HD cases and murine HD models, suggesting the role of extracellular matrices in the pathogenesis of HD. Recent studies suggest that intestinal smooth muscle cells, target cells of enteric neurons, play an important role in guiding and influencing its own innervation. Normal maturation was inhibited in neurons cultured with smooth muscle cells of aganglionic colon in comparison to normal colon. Furthermore, it was demonstrated that levels of neurotrophic factors, crucial in the development and survival of enteric neurons, are decreased in circular muscle layers of aganglionic colon in comparison to normoganglionic colon. The smooth muscle cells of the aganglionic colon may represent an unfavorable microenvironment for neuronal development compared with the normally innervated region. Recently, markedly increased immunoreactivity of major histocompatibility complex (MHC) class II antigens and ICAM-1 was demonstrated in aganglionic bowel, suggesting the immunological mechanisms may be involved in the etiology of HD. Genetic factors have been implicated in the etiology of this condition because HD is known to occur in families and in association with some chromosomal abnormalities. Recent expansion of molecular genetics identified multiple susceptibility genes of HD, including the RET gene, the glial cell line-derived neurotrophic factor gene, the endothelin-B receptor gene, and endothelin-3 gene. Of these, inactivating mutations of the RET gene are the most frequent, occurring in 50% of familial and 15% to 20% of sporadic cases of HD. To date, despite extensive research, the exact etiology of this condition remains poorly understood. The present report describes the authors' current understanding of and recent progress in the etiology of HD.
 ...
PMID:Hirschsprung's disease: a search for etiology. 971 51

Despite significant advances in understanding the genetic background in Hirschsprung's disease (HD), the majority of cases are believed to be multigenic and multifactorial. Conditions associated with an increased risk of HD suggest some common inherited factor and include Down's syndrome, Waardenburg syndrome (WS), dominant sensorineural deafness, neurofibromatosis, neuroblastoma, phaechromocytoma, the MEN type 2B syndrome, and other abnormalities. The reported incidence of Down's syndrome in HD is approximately 2%, but the range varies from 2% to 15%. WS, on the other hand, is one of a number of uncommon human conditions in which pigmentary disturbances are associated with sensorineural deafness. HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans. Mutations of known genes appear to account for only a relatively small number of HD cases (20% in the case of RET). GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET). The genetic aspects of HD occurring in association with trisomy 21 and WS are reviewed. Clinical presentation, diagnosis, treatment and long-term outcome in this patient group are evaluated. Additional data are presented on 12 children with Down's syndrome out of 408 surgically treated HD patients. The role of associated anomalies is evaluated, and an increased susceptibility to severe enterocolitis associated with a high mortality rate is reported. Surgical correction can be achieved, but patients may require some form of ongoing help to facilitate acceptable bowel function. The decision as to the nature and timing of the surgical correction must be individualized.
 ...
PMID:Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. 971 53

We report here the identification of a gene, termed GFRalpha-3 (glial cell line-derived neurotrophic factor family receptor alpha-3), related to GFRalpha-1 and GFRalpha-2 (also known as GDNFR-alpha and GDNFR-beta), and describe distribution of GDNFalpha-3 in the nervous system and other parts of the mouse body during development and in the adult. GFRalpha-3 in situ hybridization signals were found mainly in the peripheral nervous system, with prominent signals in developing dorsal root and trigeminal ganglia. Sympathetic ganglia were also positive. Developing nerves manifested strong GFRalpha-3 mRNA signals, presumably generated by the Schwann cells. Olfactory ensheathing cells were also positive. Other non-neuronal cells appearing positive during development included chromaffin cells in the adrenal gland and small clusters of cells in the intestinal epithelium. In the central nervous system no robust signals could be detected at any stage investigated with the present probes. Compared with the previously described GFRalpha-1 and GFRalpha-2 mRNAs, which are widely distributed in the central nervous system and peripheral organs, the expression of GFRalpha-3 mRNA is much more restricted. The prominent expression in Schwann cells during development suggests a key role for GFRalpha-3 in the development of the peripheral nervous system. As Schwann cells are known to lack expression of the transducing RET receptor, we propose that a possible function of GFRalpha-3 during development could be to bind Schwann cell-derived GDNF-like ligands, thus presenting such molecules to growing axons.
 ...
PMID:GFRalpha-3, a protein related to GFRalpha-1, is expressed in developing peripheral neurons and ensheathing cells. 974 4

Hirschsprung disease is a congenital malformation affecting 1 in 5000 live births. The absence of parasympathetic neuronal ganglia (Meissner, Auerbach) in the hindgut results in poor coordination of peristaltic movement, and a varying degree of constipation. Four different genes have been implicated in the pathogenesis of Hirschsprung disease: the RET tyrosine kinase receptor gene; one of its ligands, the glial cell line-derived neurotrophic factor (GDNF) gene; the endothelin receptor B (EDNRB) gene; and its ligand, endothelin-3 (EDN3). Recently, combinations of mutations in two of these genes (RET and GDNF) have been reported in Hirschsprung patients. We report a family with missense mutations in both the RET gene (R982C) and the EDNRB gene (G57S). In this family, three out of five members have the two mutations, but only one, a boy, has the Hirschsprung disease phenotype. This illustrates the complexity of the molecular background of Hirschsprung disease.
 ...
PMID:Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B). 976 Jan 96

The steady-state mRNA levels of glial cell line-derived neurotrophic factor (GDNF), GDNFR-alpha and RET were examined in various human peripheral neuropathies to determine the relationship with myelinated fiber pathology, and T cell and macrophage invasions in the diseased nerves. GDNF and GDNFR-alpha mRNA levels were elevated to variable extent in the diseased nerves, although they were not specific to the type of diseases. The increase of GDNFR-alpha mRNA levels was correlated with the extent of the nerves with axonal pathology, and was proportional to the extent of invasion of the nerves by T cells and macrophages. The GDNF mRNA levels were not related to axonal, demyelinating pathology, or inflammatory cell invasions. RET mRNA expression was not detected in normal nor diseased nerves. The GDNF and GDNFR-alpha expression in the diseased human nerves is regulated by an underlying pathology-related process, and could play a role in peripheral nerve repair.
 ...
PMID:Expression of glial cell line-derived neurotrophic factor and GDNFR-alpha mRNAs in human peripheral neuropathies. 985 8

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most frequent cause of congenital bowel obstruction. Germline mutations in the RET receptor tyrosine kinase have been shown to cause HSCR. Mice that carry null alleles for RET or for its ligand, glial cell line-derived neurotrophic factor (GDNF), both exhibit complete intestinal aganglionosis and renal defects. Recently, the Src homology 2 (SH2) domain-containing protein Grb10 has been shown to interact with RET in vitro and in vivo, early in development. We have confirmed the map location of GRB10 on human chromosome 7, isolated human BACs containing the gene, elucidated its genomic structure, isolated a highly polymorphic microsatellite marker adjacent to exon 14 and scanned the gene for mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds and no mutations were found in patients. These data suggest that while GRB10 may be important for signal transduction in developing embryos, it does not play an obvious role in HSCR.
 ...
PMID:Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10 and evaluation of its role in Hirschsprung disease. 988 9

The glial cell line-derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRalpha1-GFRalpha4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the former orphan receptor GFRalpha3-RET. Artemin is a survival factor for sensory and sympathetic neurons in culture, and its expression pattern suggests that it also influences these neurons in vivo. Artemin can also activate the GFRalpha1-RET complex and supports the survival of dopaminergic midbrain neurons in culture, indicating that like GDNF (GFRalpha1-RET) and NTN (GFRalpha2-RET), Artemin has a preferred receptor (GFRalpha3-RET) but that alternative receptor interactions also occur.
 ...
PMID:Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. 988 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>