Sox17 Regulates a Program of Oligodendrocyte Progenitor Cell Expansion and Differentiation during Development and Repair

Abstract

Summary: Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology in vivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation in vivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair. : Oligodendrocyte development is controlled by sequential processes of progenitor cell proliferation and differentiation, believed to be largely regulated by distinct mechanisms. Chew et al. characterize white matter abnormalities in brains of Sox17-deficient mice and identify the candidate Sox17-regulated target genes Notch and TCF7L2, which mediate progenitor cell expansion and maturation, respectively. Keywords: Oligodendrocyte Progenitor Cell, Oligodendrocyte, Sox17, TCF7L2, Notch, Olig2, Proliferation, Differentiation, myelination, regeneration