Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity

Notch signaling is central to vertebrate development, and analysis of Notch has provided important insights into pathogenetic mechanisms in the CNS and many other tissues. However, surprisingly little is known about the role of Notch in the development and pathology of Schwann cells and peripheral nerves. Using transgenic mice and cell cultures, we found that Notch has complex and extensive regulatory functions in Schwann cells. Notch promoted the generation of Schwann cells from Schwann cell precursors and regulated the size of the Schwann cell pool by controlling proliferation. Notch inhibited myelination, establishing that myelination is subject to negative transcriptional regulation that opposes forward drives such as Krox20. Notably, in the adult, Notch dysregulation resulted in demyelination; this finding identifies a signaling pathway that induces myelin breakdown in vivo. These findings are relevant for understanding the molecular mechanisms that control Schwann cell plasticity and underlie nerve pathology, including demyelinating neuropathies and tumorigenesi

Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell-Axon Interface and in the Initiation of Myelination

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. beta-Catenin, a downstream effector of N-cadherin, colocalizes and coimmunoprecipitates with N-cadherin on the initiation of myelination. To determine whether beta-catenin mediates compensation on N-cadherin deletion, SC-specific gene ablation of beta-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 beta-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

A role for Schwann cell-derived neuregulin-1 in remyelination

After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 NRG1) type III and, unexpectedly, also NRG1 type I restored normal myelination when overexpressed in transgenic mice. This led to the observation that Wallerian degeneration induced de novo NRG1 type I expression in Schwann cells themselves. Mutant mice lacking a functional Nrg1 gene in Schwann cells are fully myelinated but exhibit impaired remyelination in adult life. We suggest a model in which loss of axonal contact triggers denervated Schwann cells to transiently express NRG1 as an autocrine/paracrine signal that promotes Schwann cell differentiation and remyelination

Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function

The expanding phenotype of COL4A1 and COL4A2 mutations : clinical data on 13 newly identified families and a review of the literature

Two proa1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proa2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance