Transcription factor 7‐like 2 (TCF7l2) regulates CNS myelination separating from its role in upstream oligodendrocyte differentiation

Oligodendrocyte progenitor cells (OPCs) differentiation into oligodendrocytes (OLs) and subsequent myelination are two closely coordinated yet differentially regulated steps for myelin formation and repair in the CNS. Previously thought as an inhibitory factor by activating Wnt/beta-catenin signaling, we and others have demonstrated that the Transcription factor 7-like 2 (TCF7l2) promotes OL differentiation independent of Wnt/beta-catenin signaling activation. However, it remains elusive if TCF7l2 directly controls CNS myelination separating from its role in upstream oligodendrocyte differentiation. This is partially because of the lack of genetic animal models that could tease out CNS myelination from upstream OL differentiation. Here, we report that constitutively depleting TCF7l2 transiently inhibited oligodendrocyte differentiation during early postnatal development, but it impaired CNS myelination in the long term in adult mice. Using time-conditional and developmental-stage-specific genetic approaches, we further showed that depleting TCF7l2 in already differentiated OLs did not impact myelin protein gene expression nor oligodendroglial populations, instead, it perturbed CNS myelination in the adult. Therefore, our data convincingly demonstrate the crucial role of TCF7l2 in regulating CNS myelination independent of its role in upstream oligodendrocyte differentiation.