Effect of the Jimpy Mutation on Expression of Myelin Proteins in Heterozygous and Hemizygous Mouse Brain

Kerner, Ann-Louise; Carson, John H.

doi:10.1111/j.1471-4159.1984.tb06099.x

Cited by 61 publications

(37 citation statements)

References 33 publications

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“…This is consistent with other studies (21,35,38) indicating that in Tajp heterozygous females, the amounts of these proteins or their mRNAs are reduced. Sorg et al (38) reported an approximate 25% reduction in the amount of MBP mRNA in heterozygous females.…”

Section: Discussionsupporting

confidence: 82%

Characterization of myelin proteolipid mRNAs in normal and jimpy mice.

Gardinier¹,

Macklin²,

Diniak³

et al. 1986

Mol. Cell. Biol.

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A clone specific for the rat myelin proteolipid protein (PLP) was isolated from a cDNA library made in pUC18 from 17-day-old rat brain stem mRNA. This clone corresponded to the carboxyl-terminal third of the PLP-coding region. The clone was used to identify PLP-specific mRNAs in mouse brain and to establish the time course of PLP mRNA expression during mouse brain development. Three PLP-specific mRNAs were seen, approximately 1,500, 2,400, and 3,200 bases in length, of which the largest was the most abundant. During brain development, the maximal period of PLP mRNA expression was from 14 to 25 days of age, and this was a similar time course to that for myelin basic protein mRNA expression. When the jimpy mouse, an X-linked dysmyelination mutant, was studied for PLP mRNA expression, low levels of PLP mRNA were seen which were approximately 5% of wild-type levels at 20 days of age. When jimpy brain RNA was analyzed by Northern blotting, the PLP-specific mRNA was shown to be 100 to 200 bases shorter than the wild-type PLP-specific mRNA. This size difference was seen in the two major PLP mRNAs, and it did not result from a loss of polyadenylation of these mRNAs.The biosynthesis of the myelin sheath is a crucial part of nervous system development, and as a result, the developmental expression of the myelin protein genes is highly regulated. The normal pattern of myelin protein expression in rodents indicates that little myelin protein expression occurs prenatally or in neonatal animals (2,5,6,8,23,26,28) and that myelin protein synthesis and accumulation increase significantly in the brain at about 10 days after birth, reaching a peak between 15 and 22 days after birth (2,5,6,8,23).Central nervous system myelin contains two major classes of proteins, myelin basic protein (MBP) and proteolipid protein (PLP), which together constitute as much as 80% of the total myelin protein (15,30). The four MBPs that are present in rodent myelin have homologous amino acid sequences, including identical amino-and carboxyl-terminal sequences but internal segments of unique amino acid sequence (3). They are translated from four different mRNAs (50), and the four MBP mRNAs can be produced from a single MBP gene by alternative mRNA splicing (12,44). Two PLPs are present in myelin, the major PLP, which has an apparent molecular weight of 25,000, and the closely related proteolipid DM20 (1), which has an apparent molecular weight of 20,000. PLP and DM20 may have a relationship similar to that found among the four MBPs, since they have identical amino-and carboxyl-terminal sequences (46), and they are very closely related by amino acid composition and by antigenic characteristics. The expression of these myelin proteins correlates closely with the formation of myelin in the developing rat brain, and mouse mutants that are defective in myelin formation show lowered levels of these myelin proteins (4,14,20,25 expression and the genetic deficiency in the shiverer mouse myelination mutant (12,34,44). Several groups have recently isolated cDNA ...

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Section: Discussionsupporting

confidence: 82%

Characterization of myelin proteolipid mRNAs in normal and jimpy mice.

Gardinier¹,

Macklin²,

Diniak³

et al. 1986

Mol. Cell. Biol.

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“…Differences between jimpy and wild-type PLP mRNA demonstrated by Sl-nuclease protection experiments (27) are also approximately consistent with the size and position of the deletion described here. A primary defect in the PLP gene in jimpy mice is consistent with the severe reduction in PLP concentration in jimpy brains (6)(7)(8)(9) and with ultrastructural (28,29), biochemical (30), and in vitro studies (31) that indicate that the primary genetic defect is expressed in oligodendrocytes. The significantly reduced mRNA levels in the mutant (Fig.…”

Section: Discussionmentioning

confidence: 75%

“…4). Myelin proteolipid protein (PLP), or lipophilin, is of particular relevance to the jimpy mutation because it is expressed specifically in the central nervous system (5) and is one of the most severely reduced myelin constituents of jimpy brains (6)(7)(8)(9). Furthermore, the gene for PLP has been mapped to the X chromosome in both man and mouse (10).…”

mentioning

confidence: 99%

Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing.

Nave¹,

Lai²,

Bloom³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

198

113

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The mouse mutant jimpy carries an X chromosome-linked recessive gene defect that affects the formation of myelin in the central nervous system. To understand the molecular basis of the jimpy mutation, we have examined the expression of mRNAs encoding myelin proteolipid protein (PLP). PLP mRNAs were detectable in jimpy brain RNA at 21 days after birth but were severely reduced in abundance compared to wild-type littermates. Nucleotide sequence analysis of cDNA clones for PLP mRNA, isolated from a cDNA library of jimpy brain poly(A)+ RNA, revealed that the PLP mRNA expressed in jimpy contained a deletion of 74 nucleotides with respect to the wild-type sequence. This deletion causes a frameshift in the open reading frame resulting in an altered carboxyl terminus for jimpy PLP. Probes specific for the deleted sequence, however, hybridize with equal efficiency to genomic DNA from jimpy and wild-type littermates, suggesting that the defect in the jimpy PLP mRNA is generated by aberrant RNA processing rather than by deletion of genomic sequences. We conclude that a mutation in the gene for PLP that leads to an incorrectly spliced RNA transcript is the primary defect of this genetic disorder.Neurological mutants (1) are an important tool in developmental neurobiology as they may indirectly demonstrate the function of a single gene product in the development of the nervous system. In many mutant phenotypes, however, the primary defect is difficult to distinguish from secondary symptoms of the disease, and the affected gene product has been identified for only a few of the neurological mutations of the mouse. Identification of the nature of the mutation is essential for a full understanding of the molecular basis of the defect and of the role of the affected gene and its products in normal brain development.The mutant mouse jimpy (2, 3) carries an X-linked recessive genetic disorder (jp) that exclusively affects the formation of myelin in the central, but not in the peripheral, nervous system. Its first symptom, a characteristic body tremor preceding locomotor activity, appears around postnatal day 11, after the onset of myelination in the normal mouse brain. Later, convulsions develop and death occurs in the fifth week. Histological studies of jimpy mice reveal an almost complete absence of white matter in the central nervous system, and only some axons show more than a few sheaths of uncompacted myelin (4). Various biochemical abnormalities have been reported in the mutant, in particular a drastic decrease of structural myelin proteins and enzymes involved in myelin lipid metabolism (summarized in ref. 4). Myelin proteolipid protein (PLP), or lipophilin, is of particular relevance to the jimpy mutation because it is expressed specifically in the central nervous system (5) and is one of the most severely reduced myelin constituents of jimpy brains (6-9). Furthermore, the gene for PLP has been mapped to the X chromosome in both man and mouse (10). We have cloned and determined the full-length sequences of two mRNA...

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“…The hypomyelination injimpy mice is more severe than in shiverer and appears to be associated with a partial deletion of the coding region of PLP mRNA due to an aberrant splicing of the primary gene transcript (3)(4)(5)(6). PLP, an intrinsic membrane protein thought to play a role in compaction of the extracellular leaflets of CNS myelin, is absent or dramatically reduced in jimpy mice (7)(8)(9).…”

mentioning

confidence: 99%

Abnormal compact myelin in the myelin-deficient rat: absence of proteolipid protein correlates with a defect in the intraperiod line.

Duncan¹,

Hammang²,

Trapp³

1987

Proc. Natl. Acad. Sci. U.S.A.

133

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The cervical spinal cords of 23-day-old myelin-deficient (md) rats, an X chromosome-linked myelin mutant, and their normal littermates were studied by light and electron microscopy, immunocytochemistry, and in situ hybridization. Light microscopy showed that there were scattered myelinated fibers in the md rat, particularly in the lateral and ventral columns. Ultrastructural examination of these fibers showed that the myelin often had many lamellae that were tightly compacted, but in which the intraperiod line was abnormally fused at most places, resulting in a minor alteration of the myelin periodicity. Immunocytochemical staining of adjacent sections following a variety of fixation methods showed that the myelinated fibers were positive for inyelin basic protein but negative for proteolipid protein (PLP). In situ hybridization using cDNA probes to these proteins showed a severe diminution of the mRNAs for both proteins. These findings provide further support for an abnormality in genetic regulation of PLP as has been described in another X chromosome-linked mutant, the jimpy mouse. Despite the lack of PLP, however, a few myelinated fibers are formed in the md rat, but the myelin formed in general lacks a normal intraperiod line, a site at which this protein is thought to be located.Many axons in the central nervous system (CNS) are surrounded by myelin sheaths, multilamellar compact membranes produced by oligodendrocytes. How these membranes are formed and maintained on a molecular basis is unclear, but the study of perturbations of the normal myelinogenesis in myelin mutants has led to progress in unraveling this developmental process. Two molecules, myelin basic protein (MBP) and proteolipid protein (PLP), comprise -60-80o of the total proteins of CNS myelin (1). Several murine mutants display a hypomyelination of the CNS that is accompanied by a lack or dramatic reduction of MBP and/or PLP. In two of such mutants, the shiverer and jimpy mice, considerable progress has been made recently in elucidating the possible molecular basis of their hypomyelination. In the shiverer mouse there is a deletion of a large part of the gene coding MBP (2) and CNS myelin is usually poorly compacted. The CNS and peripheral nervous system (PNS) are negative for MBP when stained immunocytochemically, although the PNS appears structurally normal. The hypomyelination injimpy mice is more severe than in shiverer and appears to be associated with a partial deletion of the coding region of PLP mRNA due to an aberrant splicing of the primary gene transcript (3-6). PLP, an intrinsic membrane protein thought to play a role in compaction of the extracellular leaflets of CNS myelin, is absent or dramatically reduced in jimpy mice (7-9).The myelin-deficient (md) rat is a sex-linked recessive mutant that has a severe CNS myelin deficit similar to jimpy (10,11).Previous morphological studies have failed to find myelin in the CNS of md rats (11,12) and the number of intrafascicular oligodendrocytes appears to be reduced in regions no...

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Effect of the Jimpy Mutation on Expression of Myelin Proteins in Heterozygous and Hemizygous Mouse Brain

Cited by 61 publications

References 33 publications

Characterization of myelin proteolipid mRNAs in normal and jimpy mice.

Characterization of myelin proteolipid mRNAs in normal and jimpy mice.

Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing.

Abnormal compact myelin in the myelin-deficient rat: absence of proteolipid protein correlates with a defect in the intraperiod line.

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