Regulation and developmental expression of Periaxin in the peripheral nervous system

The Schwann cell is the major glial cell of the vertebrate peripheral nervous system (PNS) where its prime function is to ensheathe and myelinate nerve fibers. Although axons promote the differentiation of Schwann cells, the identity of the signalling molecules responsible is unknown. It is likely that the cytoskeleton plays a vital role in regulating both the changes in cell shape and the expression of myelin protein genes that are required for myelination. Hence the discovery of L- and Speriaxin, putative cytoskeletal-associated proteins of myelinating Schwann cells, has prompted a detailed examination of their localization and developmental expression in differentiating Schwann cells. In this work, in a search for proteinbinding domains which might help elucidate the function of the periaxin isoforms, a single modular PDZ protein-binding domain was identified at the extreme Nterminus. This strongly suggests that these proteins play a role in signalling axonglial interactions.The localization of L- and S-periaxin was studied in the developing axonSchwann cell unit where both proteins were localized exclusively to myelin-forming cells. During initial axonal ensheathment L-periaxin was detected at the Schwann cell plasma membrane and in uncompacted myelin whorls. In early postnatal nerve it was concentrated in the adaxonal (apposing the axon) and abaxonal (apposing the basal lamina) membranes, but as the myelin sheath matures, L-periaxin became predominantly localized to the abaxonal Schwann cell membrane demonstrating a dynamic change in localization during development and ensheathment. This shift in localization of the protein after completion of the spiralization phase of myelination suggests that it participates in stabilizing the mature mmyelin sheath. In contrast, S-periaxin was not associated with membranes but appeared to be present throughout the Schwann cell cytoplasm. Both proteins were excluded from compact myelin.During embryogenesis, Schwann cell precursor cells develop from migrating neural crest cells. At around E14.5 in the mouse sciatic nerve, the precursor cells differentiate to form embryonic Schwann cells which in turn become either myelinforming or non-myelin-forming Schwann cells in the mature PNS. In contrast to the gene encoding the major myelin protein PO, which is expressed in neural crest cells, Schwann cell precursor cells and embryonic Schwann cells, L-periaxin mRNA and protein were first detected in embryonic Schwann cells. S-periaxin was detectable somewhat later at post-natal day 1.L-periaxin was initially detected in the nuclei of embryonic Schwann cells; however it was predominantly localized to the plasma membrane by E17.5. To investigate the embryonic nuclear expression further, transfection experiments of full length and various deletion constructs of L-periaxin cDNA were undertaken which indicated that the basic domain in the N-terminus of L-periaxin was responsible for nuclear localization.The regulation of the periaxin gene was investigated by transgenesis. It was shown that a region of 5.5 kb upstream from the transcription initiation site along with the first intron could direct expression to myelinating Schwann cells as well as cells in the central nervous system indicating the presence of a neuronal silencer in the periaxin gene

Identifying the Most Significant Microbiological Foodborne Hazards to Public Health: A New Risk Ranking Model

In order to help facilitate a risk-based food safety system, we developed the Foodborne Illness Risk Ranking Model (FIRRM), a decisionmaking tool that quantifies and compares the relative burden to society of 28 foodborne pathogens. FIRRM estimates the annual number of cases, hospitalizations, and fatalities caused by each foodborne pathogen, subsequently estimates the economic costs and QALY losses of these illnesses, and, lastly, attributes these pathogen-specific illnesses and costs to categories of food vehicles, based on outbreak data and expert judgment. The model ranks pathogen-food combinations according to five measures of societal burden. FIRRM incorporates probabilistic uncertainty within a Monte Carlo simulation framework and produces confidence intervals and statistics for all outputs. Gaps in data, most importantly in regards to food attribution and the statistical uncertainty of incidence estimates, currently limit the utility of the model. Once we address these and other problems, however, FIRRM will be a robust and useful decisionmaking tool.foodborne illness, risk ranking, pathogens, health valuation, QALYs, cost of illness, uncertainty, modeling, Monte Carlo

Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(−/−);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms

Drp2 and Periaxin Form Cajal Bands with Dystroglycan But Have Distinct Roles in Schwann Cell Growth

Cajal bands are cytoplasmic channels flanked by appositions where the abaxonal surface of Schwann cell myelin apposes and adheres to the overlying plasma membrane. These appositions contain a dystroglycan complex that includes periaxin and dystrophin-related protein 2 (Drp2). Loss of periaxin disrupts appositions and Cajal bands in Schwann cells and causes a severe demyelinating neuropathy in mouse and man. Here we have investigated the role of mouse Drp2 in apposition assembly and Cajal band function and compared it to periaxin. We show that Periaxin and Drp2 are not only both required to form appositions, but they must also interact. Periaxin-Drp2 interaction is also required for Drp2 phosphorylation but phosphorylation is not required for the assembly of appositions. Drp2 loss causes corresponding increases in Dystrophin family members, utrophin and dystrophin Dp116 though dystroglycan remains unchanged. We also show that all dystroglycan complexes in Schwann cells utilise the uncleaved form of β-dystroglycan. Drp2-null Schwann cells have disrupted appositions and Cajal bands, and they undergoe focal hypermyelination and concomitant demyelination. Nevertheless, they do not have the short internodal lengths and associated reduced nerve conduction velocity seen in the absence of periaxin, showing that periaxin regulates Schwann cell elongation independent of its role in the dystroglycan complex. We conclude that the primary role of the dystroglycan complex in appositions is to stabilize and limit the radial growth of myelin