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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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.

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.