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Rapid information processing in the central nervous system requires the myelination of axons by oligodendrocytes. The transcription factor Sox2 and its close relative Sox3 redundantly regulate the development of myelin-forming oligodendrocytes, but little is known about the underlying molecular mechanisms. Here, we characterized the expression profile of cultured oligodendroglial cells during early differentiation and identified Bcas1, Enpp6, Zfp488 and Nkx2.2 as major downregulated genes upon Sox2 and Sox3 deletion. An analysis of mice with oligodendrocyte-specific deletion of Sox2 and Sox3 validated all four genes as downstream targets in vivo. Additional functional assays identified regulatory regions in the vicinity of each gene that are responsive to and bind both Sox proteins. Bcas1, Enpp6, Zfp488 and Nkx2.2 therefore likely represent direct target genes and major effectors of Sox2 and Sox3. Considering the preferential expression and role of these genes in premyelinating oligodendrocytes, our findings suggest that Sox2 and Sox3 impact oligodendroglial development at the premyelinating stage with Bcas1, Enpp6, Zfp488 and Nkx2.2 as their major effectors. [ABSTRACT FROM AUTHOR]

Oligodendrocyte development is accompanied by defined changes in the state of chromatin that are brought about by chromatin remodeling complexes. Many such remodeling complexes exist, but only a few have been studied for their impact on oligodendrocytes as the myelin-forming cells of the central nervous system. To define the role of the PBAF remodeling complex, we focused on Pbrm1 as an essential subunit of the PBAF complex and specifically deleted it in the oligodendrocyte lineage at different times of development in the mouse. Deletion in late oligodendrocyte progenitor cells did not lead to substantial changes in the ensuing differentiation and myelination processes. However, when Pbrm1 loss had already occurred in oligodendrocyte progenitor cells shortly after their specification, fewer cells entered the pre-myelinating state. The reduction in pre-myelinating cells later translated into a comparable reduction in myelinating oligodendrocytes. We conclude that Pbrm1 and, by inference, the activity of the PBAF complex is specifically required at the transition from oligodendrocyte progenitor to pre-myelinating oligodendrocyte and ensures the generation of normal numbers of myelinating oligodendrocytes. [ABSTRACT FROM AUTHOR]

Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 120 mutations of the human DES gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in the complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology are hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in the extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChRγ subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and an increased rise time of the nerve-independent miniature endplate potentials. The latter appears related to the fragmentation of NMJs in desmin knockout mice. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian NMJs. [ABSTRACT FROM AUTHOR]

Abstract: The high‐mobility‐group domain containing SoxC transcription factors Sox4 and Sox11 are expressed and required in the vertebrate central nervous system in neuronal precursors and neuroblasts. To identify genes that are widely regulated by SoxC proteins during vertebrate neurogenesis we generated expression profiles from developing mouse brain and chicken neural tube with reduced SoxC expression and found the transcription factor prospero homeobox protein 1 (Prox1) strongly down‐regulated under both conditions. This led us to hypothesize that Prox1 expression depends on SoxC proteins in the developing central nervous system of mouse and chicken. By combining luciferase reporter assays and over‐expression in the chicken neural tube with in vivo and in vitro binding studies, we identify the Prox1 gene promoter and two upstream enhancers at −44 kb and −40 kb relative to the transcription start as regulatory regions that are bound and activated by SoxC proteins. This argues that Prox1 is a direct target gene of SoxC proteins during neurogenesis. Electroporations in the chicken neural tube furthermore show that Prox1 activates a subset of SoxC target genes, whereas it has no effects on others. We propose that the transcriptional control of Prox1 by SoxC proteins may ensure coupling of two types of transcription factors that are both required during early neurogenesis, but have at least in part distinct functions. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/ [ABSTRACT FROM AUTHOR]

Oligodendrocytes produce myelin for rapid transmission and saltatory conduction of action potentials in the vertebrate central nervous system. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2. Functional interactions among them are poorly understood and important components of the regulatory network are still unknown. Here, we identify Nfat proteins as Sox10 targets and regulators of oligodendroglial differentiation in rodents and humans. Overall levels and nuclear fraction increase during differentiation. Inhibition of Nfat activity impedes oligodendrocyte differentiation in vitro and in vivo. On a molecular level, Nfat proteins cooperate with Sox10 to relieve reciprocal repression of Olig2 and Nkx2.2 as precondition for oligodendroglial differentiation and myelination. As Nfat activity depends on calcium-dependent activation of calcineurin signaling, regulatory network and oligodendroglial differentiation become sensitive to calcium signals. NFAT proteins are also detected in human oligodendrocytes, downregulated in active multiple sclerosis lesions and thus likely relevant in demyelinating disease. [ABSTRACT FROM AUTHOR]

Myelin is essential for rapid saltatory conduction and is produced by Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In both cell types the transcription factor Sox10 is an essential component of the myelin-specific regulatory network. Here we identify Myrf as an oligodendrocyte-specific target of Sox10 and map a Sox10 responsive enhancer to an evolutionarily conserved element in intron 1 of the Myrf gene. Once induced, Myrf cooperates with Sox10 to implement the myelination program as evident from the physical interaction between both proteins and the synergistic activation of several myelin-specific genes. This is strongly reminiscent of the situation in Schwann cells where Sox10 first induces and then cooperates with Krox20 during myelination. Our analyses indicate that the regulatory network for myelination in oligodendrocytes is organized along similar general principles as the one in Schwann cells, but is differentially implemented. [ABSTRACT FROM AUTHOR]

Development of oligodendrocytes and myelin formation in the vertebrate central nervous system is under control of several basic helix-loop-helix transcription factors such as Olig2, Ascl1, Hes5 and the Id proteins. The class I basic helix-loop-helix proteins Tcf3, Tcf4 and Tcf12 represent potential heterodimerization partners and functional modulators for all, but have not been investigated in oligodendrocytes so far. Using mouse mutants, organotypic slice and primary cell cultures we here show that Tcf4 is required in a cell-autonomous manner for proper terminal differentiation and myelination in vivo and ex vivo. Partial compensation is provided by the paralogous Tcf3, but not Tcf12. On the mechanistic level Tcf4 was identified as the preferred heterodimerization partner of the central regulator of oligodendrocyte development Olig2. Both genetic studies in the mouse as well as functional studies on enhancer regions of myelin genes confirmed the relevance of this physical interaction for oligodendrocyte differentiation. Considering that alterations in TCF4 are associated with syndromic and non-syndromic forms of intellectual disability, schizophrenia and autism in humans, our findings point to the possibility of an oligodendroglial contribution to these disorders., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)