The presence of Oct-6 expression in the schizophrenic subjects but not in the comparison subjects suggests that Oct-6 may provide a marker for the neuropathology associated with schizophrenia. Further, it may provide a clue to the neurodevelopmental basis of the disease and could be a reliable means to examine the developmental brain abnormalities described in this disorder.

BackgroundOctamer-binding factor 6 (Oct-6, Pou3f1, SCIP, Tst-1) is a transcription factor of the Pit-Oct-Unc (POU) family. POU proteins regulate key developmental processes and have been identified from a diverse range of species. Oct-6 expression is described to be confined to the developing brain, Schwann cells, oligodendrocyte precursors, testes, and skin. Its function is primarily characterised in Schwann cells, where it is required for correctly timed transition to the myelinating state. In the present study, we report that Oct-6 is an interferon (IFN)-inducible protein and show for the first time expression in murine fibroblasts and macrophages.ResultsOct-6 was induced by type I and type II IFN, but not by interleukin-6. Induction of Oct-6 after IFNβ treatment was mainly dependent on signal transducer and activator of transcription 1 (Stat1) and partially on tyrosine kinase 2 (Tyk2). Chromatin immunopreciptitation experiments revealed binding of Stat1 to the Oct-6 promoter in a region around 500 bp upstream of the transcription start site, a region different from the downstream regulatory element involved in Schwann cell-specific Oct-6 expression. Oct-6 was also induced by dsRNA treatment and during viral infections, in both cases via autocrine/paracrine actions of IFNα/β. Using microarray and RT-qPCR, we furthermore show that Oct-6 is involved in the regulation of transcriptional responses to dsRNA, in particular in the gene regulation of serine/threonine protein kinase 40 (Stk40) and U7 snRNA-associated Sm-like protein Lsm10 (Lsm10).ConclusionOur data show that Oct-6 expression is not as restricted as previously assumed. Induction of Oct-6 by IFNs and viruses in at least two different cell types, and involvement of Oct-6 in gene regulation after dsRNA treatment, suggest novel functions of Oct-6 in innate immune responses.

In Schwann cells (SC), myelination is controlled by the transcription factor gene Krox20/Egr2. Analysis of cis-acting elements governing Krox20 expression in SC revealed the existence of two separate elements. The first, designated immature Schwann cell element (ISE), was active in immature but not myelinating SC, whereas the second, designated myelinating Schwann cell element (MSE), was active from the onset of myelination to adulthood in myelinating SC. In vivo sciatic nerve regeneration experiments demonstrated that both elements were activated during this process, in an axon-dependent manner. Together the activity of these elements reproduced the profile of Krox20 expression during development and regeneration. Genetic studies showed that both elements were active in a Krox20 mutant background, while the activity of the MSE, but likely not of the ISE, required the POU domain transcription factor Oct6 at the time of myelination. The MSE was localised to a 1.3 kb fragment, 35 kb downstream of Krox20. The identification of multiple Oct6 binding sites within this fragment suggested that Oct6 directly controls Krox20 transcription. Taken together, these data indicate that, although Krox20 is expressed continuously from 15.5 dpc in SC, the regulation of its expression is a biphasic, axon-dependent phenomenon involving two cis-acting elements that act in succession during development. In addition, they provide insight into the complexity of the transcription factor regulatory network controlling myelination.

The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.