Neurotrophic actions of GDNF and neurturin in the developing avian nervous system and cloning and expression of their receptors

The main aim of this project was to determine the neurotrophic actions of glial cell line-derived neurotrophic factor (GDNF) and neurturin, two novel members of the transforming growth factor-beta superfamily of proteins, on neurons from the peripheral nervous system and to identify their receptors. It is found that GDNF promotes the survival of multiple populations of chicken sensory and autonomic neurons in culture throughout development. Whereas sympathetic, parasympathetic and propioceptive neurons become less responsive to GDNF with age, enteroceptive and sensory cutaneous neurons become more responsive to GDNF. GDNF mRNA is expressed in the tissues innervated by these neurons, and developmental changes in its expression in several tissues mirror the changing responses of the innervating neurons to GDNF. These results have changed the previous notion that GDNF is a highly specific neurotrophic factor for motoneurons and dopaminergic neurons. It is shown that neurturin, which is structurally related to GDNF, also promotes the in vitro survival of embryonic chicken sensory and autonomic neurons. Thus, GDNF and neurturin compose a novel subfamily of homologous neurotrophic factors with a similar pattern of activity. The cloning of chicken GDNF receptor-α (GDNFR-α) and a novel receptor termed neurturin receptor-α (NTNR-α) is reported. GDNFR-α and NTNR-α are homologous receptors linked to the membrane via a glycosyl- phosphatidylinositol linkage. It is shown that ectopic co-expression in neurons of GDNFR-α with RET (rearranged during transfection), a transmembrane receptor tyrosine kinase, confers a survival response to GDNF, but not neurturin, and that co-expression of NTNR-α with RET confers a survival response to neurturin, but not GDNF. GDNFR-α and NTNR-α mRNAs are widely expressed in the nervous system, including GDNF and neurturin responsive neurons, and in non-neuronal tissues. These findings indicate that GDNF and neurturin promote neuronal survival by signalling via similar multicomponent receptors that consist of a common transducing receptor tyrosine kinase and a member of a newly emerging family of glycosyl-phosphatidylinositol-linked receptors that confer ligand- specificity

METHYL PARATHION RESIDUES IN PROTECTIVE APPAREL FABRIC: EFFECT OF RESIDUAL SOILS ON DECONTAMINATION

This study evaluated the contribution of oily and particulate soil residue to pesticide residue removal. 100% cotton and 65% polyester/35% cotton, were artificially soiled with a standard soil. The fabrics were laundered with the same substrate fabric without soil. Initial methyl parathion contamination was not dependent on the soil level or fiber content of the fabric. Residues remaining after laundering were affected by soiling level. Pesticide residues were greater when the fabric had a heavy soil build-up even though the initial contamination had been lower. Based on these findings, protective apparel should be kept as clean as possible, with daily laundering, for the presence of soil residue affected decontamination of the fabrics

AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis

Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle

Spatially Localized Disruptions of Voltage Activated Calcium Release in Mtm1-Deficient Muscle Fibers

International audienc

GDNF is an age-specific survival factor for sensory and autonomic neurons

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Impaired Sarcoplasmic Reticulum Calcium Release In Skeletal Muscle Fibers From Myotubularin-Deficient Mice

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