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Peripheral neuropathy in mice transgenic for a human MDR3 P-glycoprotein mini-gene
J J Smit1, F Baas, J E Hoogendijk
1The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
Abstract:
We have generated mice transgenic for a human MDR3 mini-gene, under control of a hamster vimentin promoter. Expression of the MDR3 transgene was found in mesenchymal tissues, peripheral nerves, and the eye lens. These MDR3 transgenic mice have a slowed motor nerve conduction and dysmyelination of their peripheral nerves. An extensive dysmyelination in some transgenic strains results in a severe peripheral neuropathy with paresis of the hind legs. How expression of the MDR3 transgene causes these abnormalities is unknown. The MDR3 gene encodes a large glycosylated plasma membrane protein with multiple transmembrane spanning domains, which are involved in the translocation of the phospholipid phosphatidylcholine through the hepatocyte canalicular membrane. The ability of the MDR3 P-glycoprotein to alter phsopholipid distribution in the plasma membrane of Schwann cells may cause the damage. It is also possible, however, that the presence of a large glycoprotein in the cell membrane may be sufficient to severely disturb myelination of peripheral nerves.
Insights
MDR3 gene expression in mice causes peripheral nerve damage and slowed nerve conduction. This research investigates the impact of the MDR3 P-glycoprotein on myelination and nerve function.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- The MDR3 gene encodes a plasma membrane glycoprotein involved in phospholipid transport.
- Dysmyelination, or impaired myelin sheath formation, affects peripheral nerve function.
Purpose of the Study:
- To investigate the effects of human MDR3 mini-gene expression in transgenic mice.
- To determine the relationship between MDR3 expression and peripheral nerve abnormalities.
Main Methods:
- Generation of transgenic mice carrying a human MDR3 mini-gene.
- Analysis of MDR3 transgene expression patterns in various tissues.
- Assessment of nerve conduction velocity and histological examination of peripheral nerves.
Main Results:
- MDR3 transgene expression observed in mesenchymal tissues, peripheral nerves, and eye lens.
- Transgenic mice exhibited slowed motor nerve conduction and peripheral nerve dysmyelination.
- Severe peripheral neuropathy with hind leg paresis in some strains.
Conclusions:
- MDR3 transgene expression is associated with peripheral nerve damage and functional deficits.
- The mechanism may involve altered phospholipid distribution by MDR3 P-glycoprotein in Schwann cells or general membrane disruption.