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Myelination is dependent on complex reciprocal interactions between the Schwann cell (SC) and axon. Recent evidence suggests that the SC-axon interface represents a membrane specialization essential for myelination; however, the manner in which this polarized-apical domain is generated remains a mystery. The cell adhesion molecule N-cadherin is enriched at the SC-axon interface and colocalizes with the polarity protein Par-3. The asymmetric localization is induced on SC-SC and SC-axon contact. Knockdown of N-cadherin in SCs cocultured with DRG neurons disrupts Par-3 localization and delays the initiation of myelination. However, knockdown or overexpression of neuronal N-cadherin does not influence the distribution of Par-3 or myelination, suggesting that homotypic interactions between SC and axonal N-cadherin are not essential for the events surrounding myelination. To further investigate the role of N-cadherin, mice displaying SC-specific gene ablation of N-cadherin were generated and characterized. Surprisingly, myelination is only slightly delayed, and mice are viable without any detectable myelination defects. β-Catenin, a downstream effector of N-cadherin, colocalizes and coimmunoprecipitates with N-cadherin on the initiation of myelination. To determine whether β-catenin mediates compensation on N-cadherin deletion, SC-specific gene ablation of β-catenin was generated and characterized. Consistent with our hypothesis, myelination is more severely delayed than when manipulating N-cadherin alone, but without any defect to the myelin sheath. Together, our results suggest that N-cadherin interacts with β-catenin in establishing SC polarity and the timely initiation of myelination, but they are nonessential components for the formation and maturation of the myelin sheath.

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits Schwann cell (SC) migration and promotes myelination via the p75 neurotrophin receptor (NTR). Despite these recent findings, the expression, localization, and mechanism of BDNF action has yet to be determined. Here we demonstrate that the sensory neurons of the dorsal root ganglion (DRG) are a major source of BDNF during postnatal development. The expression of BDNF is initially elevated before myelination and decreases dramatically after the onset of myelination. BDNF expression is controlled in part by transcriptional regulation and the increased expression of the truncated TrkB receptor on SCs. To investigate the possible mechanism of BDNF transport and release, multicompartment Campenot chambers were used. DRG neurons transported and secreted endogenous BDNF along the surface of axons in anterograde fashion. In an attempt to enhance myelination by SCs, DRG neurons were transduced with an adenovirus to overexpress BDNF. BDNF was transported and secreted along the axons and enhanced myelination when compared with control cocultures. Together, the events surrounding the expression, localization, and mechanism of BDNF action in DRG neurons may hint at potential therapeutic implications to efficiently promote remyelination.

Cell polarity is critical in various cellular processes ranging from cell migration to asymmetric cell division and axon and dendrite specification. Similarly, myelination by Schwann cells is polarized, but the mechanisms involved remain unclear. Here, we show that the polarity protein Par-3 localizes asymmetrically in Schwann cells at the axon-glial junction and that disruption of Par-3 localization, by overexpression and knockdown, inhibits myelination. Additionally, we show that Par-3 directly associates and recruits the p75 neurotrophin receptor to the axon-glial junction, forming a complex necessary for myelination. Together, these results point to a critical role in the establishment of cell polarity for myelination.

Fluorescence digital imaging microscopy was used to develop a method that allows the continuous monitoring and quantitative measurement of a single myelin internode throughout its development. Using this technique, steroid hormones such as progesterone and dexamethasone were shown to reduce the time required for the initiation and to regulate the rate of myelin synthesis. Progesterone was capable of increasing the rate of myelin synthesis in Schwann cell/neuronal co-cultures in a dose-dependent manner. RT-PCR and in situ hydridization studies revealed that the mRNAs for P450scc and 3beta-hydroxysteroid dehydrogenase, the enzymes involved in progesterone biosynthesis, were induced at the onset of myelin synthesis. The progesterone receptor protein translocated into the nucleus of the neurons during myelin synthesis, suggesting that progesterone could also be affecting neuronal gene expression. Changes in gene expression caused by progesterone are being examined to identify additional factors that may control myelin formation.