Disease relevance of NRTN

• Both GDNF and NRTN are secreted from eye muscle located in the target and trajectory pathway of ciliary ganglion pioneer axons during the period of target innervation [1].
• Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease [2].
• Because GDNF and neurturin can rescue dopamine neurons in the animal models of Parkinson disease, as well as motoneurons in vivo, hopes have been raised that GDNF family ligands may be new drugs for the treatment of neurodegenerative diseases [3].
• Idiopathic slow transit constipation and megacolon are not associated with neurturin mutations [4].
• Expression of glial cell line-derived neurotrophic factor and neurturin in mature kidney, nephrogenic rests, and nephroblastoma: possible role as differentiating factors [5].

High impact information on NRTN

• GDNF and neurturin have shown promise in clinical trials of Parkinson's disease, and artemin is currently undergoing clinical trials for chronic pain treatment [6].
• METHODS: An adeno-associated virus-based vector encoding human neurturin (AAV2-NTN; also called CERE-120) was injected into the striatum and substantia nigra of monkeys 4 days after a unilateral intracarotid injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rendered them hemiparkinsonian [7].
• After this period, however, the synthesis of GDNF declines markedly, while that of NRTN is maintained throughout the cell death period [1].
• The RET proto-oncogene encodes a receptor tyrosine kinase for transforming growth factor-beta-related neurotrophic factors, which include GDNF and neurturin [8].
• Regulation of neuromuscular synapse development by glial cell line-derived neurotrophic factor and neurturin [9].

Biological context of NRTN

• Tissue distribution of neurturin, persephin and artemin in the human brainstem at fetal, neonatal and adult age [10].
• The data suggest that NRTN might regulate survival and differentiation of spermatocytes and spermatids, but the low penetrance indicates that either the transgene expression has not been high enough or NRTN is not as essential as GDNF for spermatogenesis [11].
• 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 [12].
• This study was conducted to evaluate tear function and ocular surface phenotype in NRTN(-/-) mice [13].
• Loss of neurturin in frog-Comparative genomics study of GDNF family ligand-receptor pairs [14].

Anatomical context of NRTN

• GDNF and NRTN appear to be essential for enteric nervous system (ENS) development in mammals, zebrafish, and other teleostean species [15].
• Using Xenopus nerve-muscle co-cultures, we show that GDNF and its family member neurturin (NRTN) facilitate the development of the neuromuscular junction (NMJ) [9].
• Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus [16].
• GDNF regulates cell fate decision of undifferentiated spermatogonia 'Science 287 (2000) 1489'. The role of NRTN was now approached by targeted overexpression in mouse testis [11].
• Glial cell-line derived neurotrophic factor and neurturin regulate the expressions of distinct miRNA precursors through the activation of GFRalpha2 [17].

Associations of NRTN with chemical compounds

• Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults [16].
• In comparison to that in age-matched NRTN(+/+) mice, aqueous tear production, tear fluorescein clearance, and corneal sensation were significantly reduced in NRTN(-/-) mice, whereas corneal permeability to AFD was significantly increased [13].

Other interactions of NRTN

• Neurturin had very similar effects as GDNF [9].
• In contrast, only NRTN treatment significantly increased 5-HT-ir cells densities at 10 ng/ml (1.3-fold), while an augmentation was seen for GDNF and PSPN at 100 ng/ml (2.4-fold and 1.7-fold, respectively) [18].
• The expression of MUC-1 and -4 mRNA by the corneal epithelium was reduced in NRTN(-/-) mice [13].
• No nucleotide changes were detected in either the endothelin-3 or neurturin genes [19].
• A rapid assay for glial cell line-derived neurotrophic factor and neurturin based on transfection of cells with tyrosine hydroxylase promoter-luciferase construct [20].

Analytical, diagnostic and therapeutic context of NRTN

• Determined by tail genomic DNA PCR, 25 NRTN(-/-) mice and 17 neurturin-normal (NRTN(+/+)) mice aged 6 weeks to 4 months were evaluated [13].
• Using competitive RT/PCR, we measured the levels of mRNAs encoding GDNF and neurturin receptors in purified neurons [21].
• Transplantation of bone marrow stromal cells containing the neurturin gene in rat model of Parkinson's disease [22].
• CONCLUSION: Treatment with neurturin at the site of cavernous nerve crush injury facilitates recovery of erectile function [23].

References