Biomedical subjects

N L Nadon

Publications and source records attributed to N L Nadon.

21 records · Page 2Linked to original sources

PubMed1995

Jimpy 4J: a new X-linked mouse mutation producing severe CNS hypomyelination.

This study describes a new sex-linked myelin mutation in the mouse, jimpy 4J (Plpjp-4J), located in or very close to the proteolipid protein (Plp) gene. The Plpjp-4J/Y phenotype includes tremor, seizures, death during the 4th postnatal week, and the most severe central nervous system hypomyelination yet described in any mouse carrying a single myelin mutation. The few myelin sheaths are present in early myelinating areas where they form clusters of thin, usually loosely wrapped membranes which show several variations of morphology at their extracellular leaflets. Numbers of mature oligodendrocytes are sharply reduced; pycnotic glial nuclei and foamy cells are numerous. Astrocytosis is a prominent feature. No PLP protein is detected by immunoblotting in Plpjp-4J/Y brain but in spinal cord a faint band is present. Myelin basic protein and characteristic myelin lipids are also sharply reduced in both brain and spinal cord. Despite the qualitative similarity of the phenotypes reported in these and previous studies, DNA analysis demonstrate that Plpjp-4J is not a recurrence of the well known Plp mouse mutations jimpy (Plpjp) or myelin synthesis deficiency (Plpjp-msd).

Animals↗

PubMed1994

A combination of PLP and DM20 transgenes promotes partial myelination in the jimpy mouse.

Mutations in the myelin proteolipid protein (PLP) gene, such as that found in the jimpy mouse, result in an abnormal structure of the myelin, severe dysmyelination, and a reduction in the number of mature oligodendrocytes. To examine the functions of the two alternatively spliced isoforms of proteolipid protein, transgenic mice were generated that express either PLP or DM20 cDNAs placed under control of the PLP upstream regulatory region. The transgenes were bred into jimpy mice, and the effect of the transgenes on the dysmyelinating phenotype was analyzed. Neither the PLP transgene nor the DM20 transgene alone had an effect on myelination in the jimpy mice. Combining the two transgenes substantially increased the number of myelinated axons, suggesting that the two alternatively spliced products of the PLP locus perform distinct functions in oligodendrocytes. The enhanced myelination was not sufficient, however, for completely correcting the dysmyelinating phenotype of the jimpy mice, nor was it accompanied by the restoration of normal levels of myelin gene expression. The inability to rescue the jimpy phenotype is most likely attributable to a dominant negative action of the abnormal proteolipid proteins present in jimpy mice. These results demonstrate the complexity of proteolipid protein function in myelination.

Alternative Splicing↗

PubMed1990

A point mutation in the proteolipid protein gene of the 'shaking pup' interrupts oligodendrocyte development.

The differentiation of the oligodendrocyte from its bipotential progenitor culminates in the production of the myelin-specific proteins and the elaboration of membrane processes that ensheath the axon. Mutations in proteolipid protein (PLP) and its alternatively spliced isoform DM-20, the major protein constituents of central nervous system myelin, are characterized by a significant reduction in the number of mature oligodendrocytes, resulting in severe hypomyelination, tremor and early death. The canine shaking pup carries such a mutation, a single base change that substitutes a proline for a histidine near the first transmembrane region of PLP and DM-20. This mutation hinders oligodendrocyte differentiation, as evidence by a splicing pattern at the PLP locus characteristic of immature oligodendrocytes. The spliced transcript expressed earliest in development, DM-20, continues to be overexpressed in shaking pup oligodendrocytes. The disruption of the normal maturation schedule in these X-linked dysmyelinating disorders suggests that PLP or DM-20 plays a fundamental role in oligodendrocyte development. We propose that, while the more abundant PLP is the primary structural component of myelin, DM-20 may be critical to oligodendrocyte maturation.

Amino Acid Sequence↗