CNTFR
Ciliary neurotrophic factor receptor subunit alpha precursor (CNTF receptor subunit alpha) (CNTFR-alpha)
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Genotypic associations between polymorphisms in the ciliary neurotrophic factor (CNTF) and CNTF receptor ([[CNTFR]]) genes and muscular strength phenotypes in 154 middle-aged men (45-49 yr) and 138 women (38-44 yr) and 99 older men (60-78 yr) and 102 older women (60-80 yr) were tested to validate earlier association studies. Allelic interaction effects were hypothesized between alleles of CNTF and [[CNTFR]]. We performed analysis of covariance with age, height, and fat-free mass (FFM) as covariates. FFM was anthropometrically estimated by the equation of Durnin-Womersley. Isometric, concentric, and eccentric torques for the knee flexors (KF) and extensors (KE) were measured using Biodex dynamometry. In the older male group, T-allele carriers of the C-1703T polymorphism in [[CNTFR]] performed significantly better on all noncorrected KF torques, whereas only noncorrected KE isometric torque at 120 degrees and concentric torque at 240 degrees/s were higher than the C/C homozygotes (P < 0.05). When age, height, and FFM were used as covariates, T-allele carriers performed only better on KE and KF isometric torque at 120 degrees (P < 0.05). Concentric KF torque at 180 degrees/s was lower in middle-aged female A-allele carriers compared with the T/T subjects for the T1069A polymorphism in [[CNTFR]]. After correction for age, height, and FFM, middle-aged female A-allele carriers exhibited lower values on all concentric KF strength measures and isometric torque at 120 degrees . There was a lack of association with the CNTF G-6A polymorphism in men, with inconclusive results for a limited number of phenotypes in women. No significant CNTF/[[CNTFR]] allele interaction effects were found. Results indicate that [[CNTFR]] C-1703T and T1069A polymorphisms are significantly associated with muscle strength in humans.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Ciliary Neurotrophic Factor
- Cohort Studies
- Female
- Gene Frequency
- Genotype
- Humans
- Knee
- Longitudinal Studies
- Male
- Middle Aged
- Muscle Strength
- Muscle, Skeletal
- Phenotype
- Receptor, Ciliary Neurotrophic Factor
- Sex Factors
- Torque
A conserved hormone response element, CNTFR-DR1 (5'-AGGTCAGAGGTCAGG-3'), has been identified in the 5th intron of the alpha component of the ciliary neurotrophic factor receptor (CNTFRalpha) gene for the human TR4 orphan receptor (TR4). Electrophoretic mobility shift assay showed a specific binding with high affinity (Kd = 0.066 nM) between TR4 and the CNTFR-DR1. A reporter gene assay using chloramphenicol acetyltransferase demonstrated that the 5th intron of CNTFRalpha has an enhancer activity which could be induced by TR4 in a dose-dependent manner. Furthermore, our in situ hybridization data showed that abundant TR4 transcripts were detected in adult brain, in regions of cortical and hippocampal neurons, as well as in many developing neural structures, including brain, spinal cord, ganglia (sympathetic and sensory), and neuronal epithelia (retinal, otic, olfactory, and gustatory). The striking similarities in the expression patterns of TR4 and CNTFRalpha in the developing and postnatal nervous systems further support the potential role of TR4 in neurogenesis. Collectively, these data suggest that the human CNTFRalpha gene could represent the first identified neural-specific gene induced by TR4.
MeSH Terms
- Adult
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Binding Sites
- Brain
- Cerebral Cortex
- Chloramphenicol O-Acetyltransferase
- Cloning, Molecular
- Conserved Sequence
- Cricetinae
- Embryonic and Fetal Development
- Enhancer Elements, Genetic
- Epithelium
- Ganglia, Sensory
- Ganglia, Sympathetic
- Gene Expression Regulation, Developmental
- Hippocampus
- Humans
- Introns
- Mice
- Molecular Sequence Data
- Nerve Tissue Proteins
- Nervous System
- Neurons
- Receptor, Ciliary Neurotrophic Factor
- Receptors, Nerve Growth Factor
- Receptors, Steroid
- Receptors, Thyroid Hormone
- Recombinant Fusion Proteins
- Sequence Homology, Nucleic Acid
- Spinal Cord
- Transcription, Genetic
The activities of ciliary neurotrophic factor (CNTF) were initially thought to be restricted to cells in the nervous system. However, the recent identification of its receptor specificity-conferring alpha component ([[CNTFR]] alpha) in skeletal muscle has provided the clue to the unexpected actions of CNTF in the periphery. In the present study, we demonstrated that the mRNA expression of [[CNTFR]] alpha in chick skeletal muscle was decreased by approximately 10-fold after nerve transection; this finding is in sharp contrast to the dramatic up-regulation observed in denervated rat muscle. As a first step toward investigating the differential regulation of [[CNTFR]] alpha in chick and rat, we examined the mRNA expression of [[CNTFR]] alpha in different types of muscle following nerve injury in young and adult animals. Our findings demonstrated that the differential expression of [[CNTFR]] alpha observed in denervated skeletal muscle of the chick and rat was not dependent on age or muscle type. The temporal profile of the changes in [[CNTFR]] alpha expression was, however, dependent on the age of the chick as well as the types of muscles. Furthermore, the low level of [[CNTFR]] alpha expression observed in denervated chick muscle recovered to almost control levels in regenerating skeletal muscle. Taken together, our findings provided the first extensive analysis on the mRNA expression of [[CNTFR]] alpha and the alpha subunit of the acetylcholine receptor in various skeletal muscles of the chick following nerve injury and regeneration.
MeSH Terms
- Aging
- Animals
- Blotting, Northern
- Chickens
- Down-Regulation
- Muscle Denervation
- Muscle Development
- Muscle, Skeletal
- Nerve Crush
- RNA, Messenger
- Rats
- Receptor, Ciliary Neurotrophic Factor
- Receptors, Nerve Growth Factor
- Regeneration
- Sciatic Nerve
- Transcription, Genetic
A full-length cDNA clone encoding for the chick CNTFR alpha (alpha component of the ciliary neurotrophic factor receptor) was isolated by screening an embryonic day 13 chick brain cDNA library with a rat CNTFR alpha probe. The isolated cDNA clone contained a approximately 2-kb insert with an open reading frame of 362 amino acids. The identification of this clone as chick CNTFR alpha was based on the homology in amino acid sequence (approximately 70%) with the rat and human CNTFR alpha. Hydropathy analysis revealed that the chick CNTFR alpha contains a hydrophobic region at the amino terminus that is typical of secretory signal peptides, as well as a hydrophobic region at the carboxyl terminus that is characteristic of glycosylphosphatidylinositol-linked proteins. The expression of chick CNTFR alpha was developmentally regulated and was widely distributed in neural tissues, such as brain and spinal cord. In the periphery, chick CNTFR alpha transcript was expressed at high levels in the skeletal muscle and was only barely detectable in the liver. Unexpectedly, the expression of chick CNTFR alpha mRNA in skeletal muscle was decreased by approximately 10-fold at 1.5 days after denervation. This is in sharp contrast to the result previously obtained with CNTFR alpha in denervated rat muscle.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Chick Embryo
- Cloning, Molecular
- Down-Regulation
- Embryonic and Fetal Development
- Humans
- Molecular Sequence Data
- Muscle Denervation
- Muscle, Skeletal
- Rats
- Receptor, Ciliary Neurotrophic Factor
- Receptors, Nerve Growth Factor