Adenomatous Polyposis Coli Regulates Oligodendroglial Development

Abstract

The expression of the gut tumor suppressor gene adenomatous polyposis coli ( Apc ) and its role in the oligodendroglial lineage are poorly understood. We found that immunoreactive APC is transiently induced in the oligodendroglial lineage during both normal myelination and remyelination following toxin-induced, genetic, or autoimmune demyelination murine models. Using the Cre/loxP system to conditionally ablate APC from the oligodendroglial lineage, we determined that APC enhances proliferation of oligodendroglial progenitor cells (OPCs) and is essential for oligodendrocyte differentiation in a cell-autonomous manner. Biallelic Apc disruption caused translocation of β-catenin into the nucleus and upregulated β-catenin-mediated Wnt signaling in early postnatal but not adult oligodendroglial lineage cells. The results of conditional ablation of Apc or Ctnnb1 (the gene encoding β-catenin) and of simultaneous conditional ablation of Apc and Ctnnb1 revealed that β-catenin is dispensable for postnatal oligodendroglial differentiation, that Apc one-allele deficiency is not sufficient to dysregulate β-catenin-mediated Wnt signaling in oligodendroglial lineage cells, and that APC regulates oligodendrocyte differentiation through β-catenin-independent, as well as β-catenin-dependent, mechanisms. Gene ontology analysis of microarray data suggested that the β-catenin-independent mechanism involves APC regulation of the cytoskeleton, a result compatible with established APC functions in neural precursors and with our observation that Apc -deleted OPCs develop fewer, shorter processes in vivo . Together, our data support the hypothesis that APC regulates oligodendrocyte differentiation through both β-catenin-dependent and additional β-catenin-independent mechanisms.