Wnt/β-catenin signaling plays a major role in the development of the nervous system and contributes to neuronal plasticity. However, its role in myelination remains unclear. Here, we identify the Wnt/β-catenin pathway as an essential driver of myelin gene expression. The selective inhibition of Wnt components by small interfering RNA or dominant-negative forms blocks the expression of myelin protein zero (MPZ) and peripheral myelin protein 22 (PMP22) in mouse Schwann cells and proteolipid protein in mouse oligodendrocytes. Moreover, the activation of Wnt signaling by recombinant Wnt1 ligand increases by threefold the transcription of myelin genes and enhances the binding of β-catenin to T-cell factor/lymphoid-enhancer factor transcription factors present in the vicinity of the MPZ and PMP22 promoters. Most important, loss-of-function analyses in zebrafish embryos show,in vivo, a key role for Wnt/β-catenin signaling in the expression of myelin genes and in myelin sheath compaction, both in the peripheral and central nervous systems. Inhibition of Wnt/β-catenin signaling resulted in hypomyelination, without affecting Schwann cell and oligodendrocyte generation or axonal integrity. The present findings attribute to Wnt/β-catenin pathway components an essential role in myelin gene expression and myelinogenesis.

Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.

Significance: Growing evidence underlines the role attributed to abnormal forms of Tau in several neurodegenerative diseases known as tauopathies, including Alzheimer’s disease, which are characterized by accumulation of oligomers and filamentous Tau inclusions in the CNS. We identify a direct interaction of the immunophilin FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52) and the pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (Tau-P301L), inducing Tau-P301L oligomerization and assembly into filaments. This interaction has a considerable impact on the progress of the tauopathy because some early aspects of the disease are rescued, in vivo, by knocking down FKBP52. Our results open a new field for the study of FKBP52 pathophysiology in tauopathic dementias, including prediction of disease phenotype and search for new types of antipathological Tau treatments.