Sox2 expression in Schwann cells inhibits myelination in vivo and induces influx of macrophages to the nerve

Correct myelination is crucial for the function of the peripheral nervous system. Both positive and negative regulators within the axon and Schwann cell function to ensure the correct onset and progression of myelination during both development and following peripheral nerve injury and repair. The Sox2 transcription factor is well known for its roles in the development and maintenance of progenitor and stem cell populations, but has also been proposed in vitro as a negative regulator of myelination in Schwann cells. We wished to test fully whether Sox2 regulates myelination in vivo and show here that sustained Sox2 expression in vivo blocks myelination in the peripheral nerves and maintains Schwann cells in a proliferative non-differentiated state, associated also with increased inflammation within the nerve. The plasticity of Schwann cells allows them to re-myelinate regenerated axons following injury and we show that re-myelination is also blocked by Sox2 expression in Schwann cells. These findings identify Sox2 as a physiological regulator of Schwann cell myelination in vivo and its potential to play a role in disorders of myelination in the peripheral nervous system

Unsupervised assessment of microarray data quality using a Gaussian mixture model

<p>Abstract</p> <p>Background</p> <p>Quality assessment of microarray data is an important and often challenging aspect of gene expression analysis. This task frequently involves the examination of a variety of summary statistics and diagnostic plots. The interpretation of these diagnostics is often subjective, and generally requires careful expert scrutiny.</p> <p>Results</p> <p>We show how an unsupervised classification technique based on the Expectation-Maximization (EM) algorithm and the naïve Bayes model can be used to automate microarray quality assessment. The method is flexible and can be easily adapted to accommodate alternate quality statistics and platforms. We evaluate our approach using Affymetrix 3' gene expression and exon arrays and compare the performance of this method to a similar supervised approach.</p> <p>Conclusion</p> <p>This research illustrates the efficacy of an unsupervised classification approach for the purpose of automated microarray data quality assessment. Since our approach requires only unannotated training data, it is easy to customize and to keep up-to-date as technology evolves. In contrast to other "black box" classification systems, this method also allows for intuitive explanations.</p

Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation

Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot-Marie-Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively. This study was designed to elucidate disease processes caused by misexpression of Pmp22 and, at the same time, to gain further information on the controversial molecular function of PMP22. To this end, we took advantage of the unique resource of a set of various Pmp22 mutant mice to carry out comparative expression profiling of mutant and wild-type sciatic nerves. Tissues derived from Pmp22-/- ("knockout"), Pmp22tg (increased Pmp22 copy number), and Trembler (Tr; point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. Interestingly, the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms. Increased expression of genes involved in cell cycle regulation and DNA replication is characteristic and specific for the early stage in Pmp22-/- mice, supporting a primary function of PMP22 in the regulation of Schwann cell proliferation. In the Tr mutant, a distinguishing feature is the high expression of stress response genes. Both Tr and Pmp22tg mice show strongly reduced expression of genes important for cholesterol synthesis at P4, a characteristic that is common to all three mutants at P60. Finally, we have identified a number of candidate genes that may play important roles in the disease process or in myelination per se

Cell uptake and radiotoxicity studies of an nuclear localization signal peptide-intercalator conjugate labeled with [99mTc(CO)3]+.

A trifunctional bioconjugate consisting of the SV40 nuclear localization signal (NLS) peptide, an aliphatic triamine ligand, and the DNA intercalating pyrene has been synthesized and quantitatively labeled with [(99m)Tc(OH(2))(3)(CO)(3)](+). The radiotoxicity of the resulting nucleus-targeting radiopharmaceutical on B16F1 mouse melanoma cells has been investigated to evaluate the activity of Auger and Coster-Kronig electrons on the viability of cells. We found a dose-dependent significant radiotoxicity of the nucleus-targeting radiopharmaceutical clearly related to the low energy decay of (99m)Tc. These principal results imply a possible therapeutic strategy based on the use of the low-energy Auger electron-emitting (99m)Tc radionuclide attached to nucleus-targeting molecules and comprising an intercalator. Highly efficient DNA targeting vectors could complement the usual role of (99m)Tc in diagnostic applications. The Auger electrons emitted by the (99m)Tc nuclide induce DNA damage leading ultimately, through a mitotic catastrophe pathway, to necrotic cell death. Non-DNA-targeting (99m)Tc complexes display much lower radiotoxicity

Aging of myelinating glial cells predominantly affects lipid metabolism and immune response pathways

Both the central and the peripheral nervous systems are prone to multiple age-dependent neurological deficits, often attributed to still unknown alterations in the function of myelinating glia. To uncover the biological processes affected in glial cells by aging, we analyzed gene expression of the Schwann cell-rich mouse sciatic nerve at 17 time points throughout life, from day of birth until senescence. By combining these data with the gene expression data of myelin mouse mutants carrying deletions of either Pmp22, SCAP, or Lpin1, we found that the majority of age-related transcripts were also affected in myelin mutants (54.4%) and were regulated during PNS development (59.5%), indicating a high level of overlap in implicated molecular pathways. The expression profiles in aging copied the direction of transcriptional changes observed in neuropathy models; however, they had the opposite direction when compared with PNS development. The most significantly altered biological processes in aging involved the inflammatory/immune response and lipid metabolism. Interestingly, both these pathways were comparably changed in the aging optic nerve, suggesting that similar biological processes are affected in aging of glia-rich parts of the central and peripheral nervous systems. Our comprehensive comparison of gene expression in three distinct biological conditions including development, aging, and myelin disease thus revealed a previously unanticipated relationship among themselves and identified lipid metabolism and inflammatory/immune response pathways as potential therapeutical targets to prevent or delay so far incurable age-related and inherited forms of neuropathies