Abstract
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.
Highlights
Oligodendrocytes represent one of the main cell types in the vertebrate central nervous system (CNS)
In case of Tcf4, presence was confirmed on the protein level in Pdgfra-positive oligodendrocyte precursor cells (OPCs), O4-positive pre-myelinating and Mbp-positive myelinating oligodendrocytes by immunocytochemical staining of cultured rat oligodendroglial cells (Figure 1D)
We show that Tcf4 is required for proper terminal differentiation of oligodendrocytes and CNS myelination in vivo and ex vivo
Summary
Oligodendrocytes represent one of the main cell types in the vertebrate central nervous system (CNS). Oligodendrocytes are of neuroectodermal origin and develop from neuroepithelial progenitor cells of the ventricular zone in an ordered series of events This includes specification to oligodendrocyte precursor cells (OPCs), and expansion of the OPC population, followed by progression to pre-myelinating and eventually myelinating oligodendrocytes during terminal differentiation [1]. Many of these steps are regulated on the transcriptional level by a complex network that contains several basic helix-loop-helix (bHLH) transcription factors as central components [2,3]. Members of classes II, V and VI have so far been shown to influence oligodendrocyte development [5] This includes the class II bHLH protein Olig, which is expressed throughout oligodendroglial development and required from specification to terminal differentiation [6,7]. The class V proteins Id2 and Id4 as well as the class VI protein Hes influence oligodendroglial development as transcription factors that maintain OPCs in the proliferative state and counteract differentiation [10,11,12]
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