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

Hirschsprung disease is a congenital disorder with the incidence of 1 per 5000 live births, characterized by the absence of intestinal ganglion cells. In the etiology of Hirschsprung disease various genes play a role; these are: RET, EDNRB, GDNF, EDN3 and SOX10, NTN3, ECE1, Mutations in these genes may result in dominant, recessive or multifactorial patterns of inheritance. Diverse models of inheritance, co-existence of numerous genetic disorders and detection of numerous chromosomal aberrations together with involvement of various genes confirm the genetic heterogeneity of Hirschsprung disease. Hirschsprung disease might well serve as a model for many complex disorders in which the search for responsible genes has only just been initiated. It seems that the most important role in its genetic etiology plays the RET gene, which is involved in the etiology of at least four diseases. This review focuses on recent advances of the importance of RET gene in the etiology of Hirschsprung disease.
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PMID:[The role of ret gene in the pathogenesis of Hirschsprung disease]. 1585 39

Molecular mechanisms that lead to congenital anomalies of kidneys and the lower urinary tract (CAKUT) are poorly understood. To elucidate the molecular basis for signaling specificity of GDNF-mediated RET signaling in kidney development, we characterized mice that exclusively express either the human RET9 or RET51 isoform, or express these isoforms with individual mutations in docking tyrosines for PTB and SH2-domain-containing adaptors Src (Y981), PLCgamma (Y1015), and Shc (Y1062). Our results provide evidence for differential and isoform-specific roles of these docking sites in murine kidney development. Homozygous Ret(RET9) and Ret(RET51) mice were viable and show normally developed kidneys, indicating redundant roles of human RET isoforms in murine kidney development. In the context of the RET51 isoform, only mutation of the docking Tyr 1015 (Y1015F) resulted in severe renal anomalies. These included bilateral megaureters and multicystic kidneys that were caused by supernumerary ureteric buds that fail to separate from the wolffian duct as well as decreased branching morphogenesis. Similar kidney and ureter defects were observed in RET9(Y1015F) mice that contain the Y1015F mutation in the RET9 isoform. Interestingly, loss of RET9(Y1062)-mediated AKT/MAPK activation resulted in renal agenesis or kidney rudiments, whereas mutation of this residue in RET51 had no obvious effect on AKT/MAPK activity and renal development. These results reveal novel roles of key RET-dependent signaling pathways in embryonic kidney development and provide murine models and new insights into the molecular basis for CAKUT.
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PMID:Critical and distinct roles for key RET tyrosine docking sites in renal development. 1645 4

Our previous studies have revealed the involvement of signaling pathways of BDNF and NT-4/5 via TrkB in the development, regeneration, survival and maintenance of the Ruffini endings, primary mechanoreceptors in the periodontal ligament. However, the involvement of other neurotrophins remains unclear. The present study examined the expression of GDNF, GFRalpha1, and RET in the incisor periodontal ligament and trigeminal ganglion of young rats by RT-PCR and immunocytochemistry. All these mRNAs were detected in both tissues by RT-PCR. These immunoreactions were found in the terminal Schwann cells associated with the periodontal Ruffini endings, as confirmed by histochemistry for non-specific cholinesterase activity. Their axonal branches showed GFRalpha1- and RET-immunoreactions but lacked GDNF-immunoreactivity. In the trigeminal ganglion, about 30% of the neurons were immunoreactive to GFRalpha1 and RET. Averages of cross-sectional areas of their positive neurons demonstrated that they could mainly be categorized as medium-sized neurons. GDNF-immunoreaction was restricted to the satellite cells and not in trigeminal ganglion neurons. These findings indicate that GDNF mediates trophic effects on the survival and target innervation of the periodontal Ruffini endings via GFRalpha1 and RET.
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PMID:Expression of GDNF and its receptors in the periodontal mechanoreceptor. 1651 66

Apoptotic cell death of photoreceptors is the final event leading to blindness in the heterogeneous group of inherited retinal degenerations. GDNF (glial cell-line-derived neurotrophic factor) was found to rescue photoreceptor function and survival very effectively in an animal model of retinal degeneration (M. Frasson, S. Picaud, T. Leveillard, M. Simonutti, S. Mohand-Said, H. Dreyfus, D. Hicks, and J. Sahel, Investig. Ophthalmol. Vis. Sci. 40:2724-2734, 1999). However, the cellular mechanism of GDNF action remained unresolved. We show here that in porcine retina, GDNF receptors GFRalpha-1 and RET are expressed on retinal Mueller glial cells (RMG) but not on photoreceptors. Additionally, RMG express the receptors for the GDNF family members artemin and neurturin (GFRalpha-2 and GFRalpha-3). We further investigated GDNF-, artemin-, and neurturin-induced signaling in isolated primary RMG and demonstrate three intracellular cascades, which are activated in vitro: MEK/ERK, stress-activated protein kinase (SAPK), and PKB/AKT pathways with different kinetics in dependence on stimulating GFL. We correlate the findings to intact porcine retina, where GDNF induces phosphorylation of ERK in the perinuclear region of RMG located in the inner nuclear layer. GDNF signaling resulted in transcriptional upregulation of FGF-2, which in turn was found to support photoreceptor survival in an in vitro assay. We provide here a detailed model of GDNF-induced signaling in mammalian retina and propose that the GDNF-induced rescue effect on mutated photoreceptors is an indirect effect mediated by retinal Mueller glial cells.
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PMID:GDNF family ligands trigger indirect neuroprotective signaling in retinal glial cells. 1653 17

Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. All eight genes are involved in the early development of the enteric nervous system, and most act through two distinct biochemical pathways mediated by RET and EDNRB. Mutations in RET and EDNRB account for up to 50% and 5% of HSCR cases in the general population, respectively. Interaction between these two signaling pathways could modify RET expression and, therefore, HSCR phenotype. Here, we report the case of a 1-year-old Taiwanese boy who presented with abdominal distension since birth and bilious vomiting after feeding. HSCR (short-segment type) was diagnosed based on X-ray, lower gastrointestinal series and biopsy findings. Mutation analysis revealed a heterozygous T>C missense mutation in exon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90 residue in the extracellular domain of the G protein-coupled receptor with an arginine residue (C90R). No RET gene mutation was detected in this patient.
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PMID:A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease. 1661 17

The neurotrophic growth factor artemin binds selectively to GDNF family receptor alpha3 (GFRalpha3), forming a molecular complex with the co-receptor RET which mediates downstream signaling. This signaling pathway has been demonstrated to play an important role in the survival and maintenance of nociceptive sensory neurons and in the development of sympathetic neurons. However, the presence and potential role of this artemin-responsive pathway in non-neural tissues has not been fully explored to-date. To study the distribution of GFRalpha3 and RET in adult rat and human non-neural tissues, we carried out a comprehensive immunohistochemical study. We stained major organs from the digestive, urinary, reproductive, immune, respiratory and endocrine systems, and from other systems (cardiovascular, skeletal muscle), as well as regions of the nervous system for comparison. In both rat and human, the majority of non-neural cells did not exhibit detectable GFRalpha3-like immunoreactivity. In the rat, GFRalpha3- and RET-like staining were found in the same non-neural cell type only in kidney. In the human digestive and reproductive systems, a subset of epithelial cells exhibited GFRalpha3- and RET-like staining, suggesting co-localization. In other tissues, sub-populations of cells expressed either GFRalpha3- or RET-like immunoreactivity. The functional consequences of GFRalpha3 expression in non-neural cells remain to be determined.
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PMID:Distribution of GDNF family receptor alpha3 and RET in rat and human non-neural tissues. 1677 24

Four different ligand-receptor binding pairs of the GDNF (glial cell line-derived neurotrophic factor) family exist in mammals, and they all signal via the transmembrane RET receptor tyrosine kinase. In addition, GRAL (GDNF Receptor Alpha-Like) protein of unknown function and Gas1 (growth arrest specific 1) have GDNF family receptor (GFR)-like domains. Orthologs of the four GFRalpha receptors, GRAL and Gas1 are present in all vertebrate classes. In contrast, although bony fishes have orthologs of all four GDNF family ligands (GFLs), one of the ligands, neurturin, is absent in clawed frog and another, persephin, is absent in the chicken genome. Frog GFRalpha2 has selectively evolved possibly to accommodate GDNF as a ligand. The key role of GDNF and its receptor GFRalpha1 in enteric nervous system development is conserved from zebrafish to humans. The role of neurturin, signaling via GFRalpha2, for parasympathetic neuron development is conserved between chicken and mice. The role of artemin and persephin that signal via GFRalpha3 and GFRalpha4, respectively, is unknown in non-mammals. The presence of RET- and GFR-like genes in insects suggests that a ProtoGFR and a ProtoRET arose early in the evolution of bilaterian animals, but when the ProtoGFL diverged from existing transforming growth factor (TGFbeta)-like proteins remains unclear. The four GFLs and GFRalphas were presumably generated by genome duplications at the origin of vertebrates. Loss of neurturin in frog and persephin in chicken suggests functional redundancy in early tetrapods. Functions of non-mammalian GFLs and prechordate RET and GFR-like proteins remain to be explored.
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PMID:Evolution of the GDNF family ligands and receptors. 1691 71

Four different GDNF family ligand (GFL)-receptor (GFRalpha) binding pairs exist in mammals, and they all signal via the RET receptor tyrosine kinase. However, the evolution of these molecules is poorly understood. We identified orthologs of all four GFRalpha receptors and GRAL (GDNF Receptor Alpha-Like) in all vertebrate classes, and a predicted GFR-like protein in several invertebrates. In addition, Gas1 (growth arrest-specific 1), a distant member of the GFR-superfamily, is present in both vertebrates and invertebrates. Analysis of exon structures suggests a common origin of GFR-superfamily proteins and early divergence of Gas1 from the common ancestor. Bony fishes have orthologs of all four mammalian GFLs, consistent with genome duplications in early vertebrates. Surprisingly, the clawed frog and chicken have only three GFLs: synteny analysis indicates loss of neurturin in frog and of persephin in chicken. Evolutionary trace analysis and protein structure homology modeling points at GDNF as the endogenous ligand of frog GFRalpha2.
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PMID:Loss of neurturin in frog--comparative genomics study of GDNF family ligand-receptor pairs. 1715 29

Our recent study revealed an intense immunoreaction for GDNF and its receptors in the Ruffini endings, primary mechanoreceptors in the periodontal ligament, of young rats. However, no information is available for the expression of GDNF and its receptors during their development. The present study aimed to reveal postnatal changes in the immuno-expression of GDNF, GFRalpha1 and RET in the periodontal Ruffini endings of the rat incisors by double immunofluorescent staining. At postnatal day 3 (PO 3d), no structure with GDNF-, GFRalpha1-, or RET-immunoreaction existed in the periodontal ligament. The PGP 9.5-positive nerve fibers without GDNF- and RET-immunoreaction displayed a dendritic fashion at PO 1w, with a GFRalpha1-reaction found around these nerves. At PO 2w, GDNF-positive terminal Schwann cells occurred near the thick and dendritic axons, a part of which showed a RET-reaction, with no reactive cells near the thin nerves. The terminal Schwann cells became positive for GFRalpha1, but lacked RET-immunoreaction. At PO 3w, when the formation of the periodontal Ruffini endings had proceeded, GDNF-positive terminal Schwann cells began to increase in number. This stage-specific immuno-expression pattern suggests that GDNF is a key molecule for the maturation and maintenance of the periodontal Ruffini endings.
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PMID:Involvement of GDNF and its receptors in the maturation of the periodontal Ruffini endings. 1717 38

Hypoganglionosis comprises 3-5% of gastrointestinal innervation defects which are connected to therapy-resistant chronic constipation in children and adults. Similar to Hirschsprung's disease, hypoganglionosis may be complicated by megacolon formation and must be considered in the differential diagnosis. Three main subtypes may be distinguished: congenital hypoplastic hypoganglionosis occurs predominantly in Hirschsprung's disease proximal to the aganglionic segment and consists of small paucicellular ganglia with increased interganglionic distances. Oligoneuronal dysganglionic hypoganglionosis manifests in childhood. Initially, myenteric ganglia are of normal size and have normal interganglionic spacing and normal neuronal content. However, nerve cells are hypoplastic and ganglia undergo progressive nerve cell loss. This type of hypoganglionosis may progress into atrophic hypoganglionosis, which shows a morphology similar to hypoplastic hypoganglionosis. All subtypes of hypoganglionosis result in decreased acetylcholinesterase activity in the nerve fiber network of the muscularis propria. The pathogenesis of hypoganglionosis is still poorly understood. In Hirschsprung associated hypoganglionosis, mutations in the RET and GDNF-genes have been found. Despite a heterozygote GDNF+/- animal model for hypoganglionosis, no GDNF mutations have so far been demonstrated in human Hirschsprung independent, isolated hypoganglionosis.
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PMID:[Hypoganglionosis as a cause of chronic constipation]. 1727 19


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