hardly survived beyond P21 (Fig. 3a). The optic nerve, a myelinated white matter, was translucent from mutant mice (Fig. 3b), indicating a severe deficiency in myelin formation. We did notice a measurable hypomyelination in the heterogenous mice (Supplementary Fig. 3d). We further examined the ultrastructure of myelin sheath by electron microscopy. In contrast to the large number of myelinated axons in the controls at P14, myelinated axons were hardly detectable in the mutant optic nerve (Fig. 3c, d) and spinal cord (Supplementary Fig. 3e, f). In addition, the expression of myelin gene Plp1 was drastically diminished in the brain (Fig. 3e, f) and spinal cord (Supplementary Fig. 3g, h) of the mutant mice. Consistently, the level of MBP was similarly reduced in the mutant brain (Fig. 3g) and spinal cord (Supplementary Fig. 3i). Meanwhile, the differentiated OL marker CC1 was diminished in the brain (Fig. 3h, i) and spinal cord (Supplementary Fig. 3j, k) due to Setdb1 deletion. Noteworthy, Setdb1 inactivation in the OL lineage did not lead to notable alterations in neurons (Supplementary Fig. 4a, d), astrocytes (Supplementary Fig. 4b, d) or microglia (Supplementary Fig. 4c, d). Together, these observations demonstrate the essential role of SETDB1 in myelination.
