Figure 5.
Overexpression of activated β-catenin in oligodendrocyte lineage cells during development leads to hypomyelination and a significant delay in OLPs to oligodendrocyte differentiation, without affecting the embryonic production of premyelinating OLP. (A) Overexpression of activated β-catenin in oligodendrocyte lineage cells in Olig2cre/DA-Cat mice does not affect the production of premyelinating PDGFRα-expressing OLPs (arrows) in spinal cord at developmental stage E18. (B) Tcf4 protein is not expressed in the spinal cords of wild-type (WT) or Olig2cre/DA-Cat mice at E18, indicating that the Tcf4/activated β-catenin complex does not affect embryonic production of oligodendrocyte lineage cells, but appears at P1 both in the presumptive white matter in a subset of Olig2 cells (arrowheads). (C) At P15 there is a reduction in the number of Olig2 cells in spinal cord of the Olig2cre/DA-Cat, and Tcf4 is expressed in a higher proportion [(*) P = 3.8 × 10−5) of the Olig2-expressing cells. (D,G) Olig2cre/DA-Cat mice show a marked reduction [(G) (*) P = 0.0002 at P9; (**) P = 5.5 × 10−5 at P15] in the number of mature oligodendrocytes expressing PLP message during myelination at P9 and P15, with a clear reduction in the white matter visible under dark field (DF) at P15. (E,H) Ataxia and tremor are associated with a significant hypomyelination in Olig2cre/DA-Cat mice, as seen by EM in the P15 spinal cord white matter, and a significant (P = 1.9 × 10−35) reduction in the myelin thickness as assessed by G-ratio analysis. (F,I) The hypomyelination during developmental myelination in Olig2cre/DA-Cat represents a delay in OLP differentiation rather than an irreversible block; myelin appearance and G-ratio are similar to wild-type littermates in the adult P50 white matter.