Proteolipid protein (PLP) and its smaller isoform DM20 constitute the major myelin proteins of the CNS. Mutations of the X‐linked Plp gene cause the heterogeneous syndromes of Pelizaeus‐Merzbacher disease (PMD) and spastic paraplegia (SPG) in man and similar dysmyelinating disorders in a range of animal species. A variety of mutations including missense mutations, deletions, and duplications are responsible. Missense mutations cause a predicted alteration in primary structure of the encoded protein(s) and are generally associated with early onset of signs and generalised dysmyelination. The severity of the phenotype varies according to the particular codon involved and the influence of uncharacterised modifying genes. There is some evidence that the dysmyelination results from the altered protein acquiring a novel function deleterious to the oligodendrocyte's function. Transgenic mice carrying extra copies of the Plp gene provide a valid model of PMD/SPG due to gene duplication. Depending on the gene dosage, the phenotype can vary from early onset of severe and lethal dysmyelination through to a very late onset of a tract‐specific demyelination and axonal degeneration. Mice with a null mutation of the Plp gene assemble and maintain normal amounts of myelin but develop a progressive axonopathy, again demonstrating tract specificity. The results indicate that the functions of PLP are far from clear. There is good evidence that it is involved in the formation of the intraperiod line of myelin, and the results from the knockout and transgenic mice suggest a role in the interaction of oligodendrocyte and axon. Microsc. Res. Tech. 41:344–358, 1998. © 1998 Wiley‐Liss, Inc.

The transcription factors Emx2 and Pax6 are expressed in the proliferating zones of the developing rodent neocortex, and gradients of expression interact in specifying caudal and rostral identities. Pax6 is also involved in corticoneurogenesis, being expressed by radial glial progenitors that give rise to cells that also sequentially express Tbr2, NeuroD and Tbr1, genes temporally downstream of Pax6. In this study, using in situ hybridization, we analysed the expression of EMX2, PAX6, TBR2, NEUROD and TBR1 mRNA in the developing human cortex between 8 and 12 postconceptional weeks (PCW). EMX2 mRNA was expressed in the ventricular (VZ) and subventricular zones (SVZ), but also in the cortical plate, unlike in the rodent. However, gradients of expression were similar to that of the rodent at all ages studied. PAX6 mRNA expression was limited to the VZ and SVZ. At 8 PCW, PAX6 was highly expressed rostrally but less so caudally, as has been seen in the rodent, however this gradient disappeared early in corticogenesis, by 9 PCW. There was less restricted compartment-specific expression of TBR2, NEUROD and TBR1 mRNA than in the rodent, where the gradients of expression were similar to that of PAX6 prior to 9 PCW. The gradient disappeared for TBR2 by 10 PCW, and for NEUROD and TBR1 by 12 PCW. These data support recent reports that EMX2 but not PAX6 is more directly involved in arealization, highlighting that analysis of human development allows better spatio-temporal resolution than studies in rodents.

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Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report converging evidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7-a kinase activated by glutamatergic activity. While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios: ~1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value: 3 × 10(-4)). While some caution is warranted until these association data are further replicated, these results are the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in human PFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.

The morphological differentiation of oligodendrocytes is characterized by the formation of multiple, microtubule-rich processes which endow these cells with the ability to myelinate many axons simultaneously. Since microtubule-associated proteins (MAPs) strongly influence the structure and function of microtubules, we have investigated their expression in cultured differentiating oligodendrocytes in order to gain insights into MAP function during process formation and stabilization. MAP1B has been compared with two other structural MAPs: MAP4, which is an ubiquitously expressed protein, and MAP2, which hitherto was thought to be confined to neurons and reactive astrocytes. Immunofluorescence microscopy showed that the colocalization of MAP4 with microtubules in oligodendrocyte processes is not as extensive as found previously for MAP1B (Vouyiouklis and Brophy: J Neurosci Res 35:257-267, 1993). Nevertheless, like MAP1B, the expression of MAP4 increases during oligodendrocyte differentiation. In contrast, the expression of MAP2 is transiently elevated in preoligodendrocytes but declines precipitously at the onset of terminal differentiation. Cells of the oligodendrocyte lineage exclusively express a novel isoform of MAP2c which is primarily localized in the cell bodies of preoligodendrocytes. This suggests that MAP2c assists in the initiation of process extension rather than in the stabilization of microtubules in the cytoplasm-filled membranous extensions of mature cells. MAP-tau was not expressed at any developmental stage by oligodendrocytes. The distinct subcellular localizations and patterns of developmental expression of MAP1B, MAP4, and MAP2c suggest that these MAPs have different roles in the regulation of the microtubule network during the differentiation of myelin-forming oligodendrocytes.

Two isoforms of the Ca2+‐sensitive, actin‐binding protein gelsolin have been identified thus far; one is an intracellular protein, cytoplasmic gelsolin, and the other is a secretory protein called plasma gelsolin. Gelsolin expression in the mammalian CNS appears to be localized mainly to oligodendrocytes where it is presumed that the cytoplasmic isoform predominates. Here, we show that oligodendrocytes not only contain cytoplasmic gelsolin, but they also express a novel gelsolin isoform that we have named gelsolin‐3. Cytoplasmic gelsolin, plasma gelsolin, and gelsolin‐3 arise by alternative splicing from the same gene. The N‐terminal amino acid sequence unique to gelsolin‐3 is shown to be encoded by a single exon in a region previously thought to be an intron in the human gelsolin gene. In situ hybridization analysis confirmed that gelsolin‐3 mRNA is localized primarily to oligodendrocytes in rat brain. In other tissues, gelsolin‐3 shows a more restricted pattern of expression than cytoplasmic gelsolin. These data support the view that the gelsolin isoforms have differential roles in the regulation of the actin cytoskeleton.

Alternative splicing of the precursor for messenger RNA (pre-mRNA) is a common process utilised by higher eukaryotes to modulate gene expression. A single primary transcript may generate several proteins with distinct functions, expressed in tissue-specific, developmental patterns. This article describes an oligodendrocyte-specific pre-mRNA product of proteolipid protein gene (Plp) transcription, which is the precursor for Plp but not Dm20 mRNA in the CNS. This Plp-specific pre-mRNA (Ppm-1) includes the intact intron 3 of the Plp gene. It is first expressed during active myelination, and it localises to the nucleus of oligodendrocytes, in both normal and jimpy ( jp) murine CNS. In addition to mouse, Ppm-1 is found also in rat and dog, but not toad or trout. Our work suggests that alternative splicing of the Plp gene primary transcript follows a branching pattern, resulting in the presence of at least one Plp isoform-specific pre-mRNA molecule, Ppm-1. Therefore, Dm20 mRNA may be the product of a divergent set of pre-mRNA splicing events.

Although proteolipid protein (PLP) and its DM20 isoform are the major membrane proteins of CNS myelin, their absence causes surprisingly few developmental defects. In comparison, missense mutations of the X-linked Plp gene cause severe dysmyelination. Previous studies have established roles for PLP/DM20 in the formation of the intraperiod line and in maintaining axonal integrity. We now show that a normal number of oligodendrocytes are present in mice lacking PLP/DM20. However, in heterozygous females, which are natural chimeras for X-linked genes, oligodendrocytes lacking PLP/DM20 are in direct competition with wild-type oligodendrocytes that have a distinct advantage. PLP+ oligodendrocytes and PLP+ myelin sheaths make up the greater majority, and this feature is generalised in the CNS throughout life. Moreover, in the absence of PLP/DM20, a proportion of small-diameter axons fails to myelinate, remaining ensheathed but lacking a compact sheath, or show delayed myelination. These findings suggest that PLP/DM20 is also involved in the early stages of axon-oligodendrocyte interaction and wrapping of the axon.