These defects are accompanied by prolonged visual signal transduction. We speculate that this mechanism that safeguards myelin integrity during early development might also play roles in myelin breakdown during neurodegeneration, where dysmyelination is a hallmark.

Through CUT&RUN and phenotypic analysis, we found that this is through TFEB-dependent autophagy, which facilitates the excessive/abnormal myelin removal during the rapid axon ensheathment phase (when oligodendrocytes are expanding their myelin membrane to ensheath axons).

Using sparse genetic deletion and labeling, we confirmed the cell-autonomous role of Tfeb in limiting myelin protrusion formation in newly formed oligodendrocytes. This is through a newly developed mouse line (Enpp6-CreERT2) that is specifically expressed in premyelinating OLs.

This can also be visualized using simple immunohistochemistry of early postnatal optic nerves. The newly formed MBP+ myelin sheaths are not smooth structures, but instead decorated with numerous myelin protrusions.

In collaboration with Mark Ellisman's lab, we used volume electron microscopy to reconstruct myelination of developing optic nerves. Surprisingly, majority of those myelin whorls are attached to myelinated axons and are within oligodendrocytes cytoplasm.

Using transmission electron microscopy, we found that optic nerves harbor numerous myelin abnormalities (whorls) during development, and that conditional deletion of an oligodendrocyte-enriched transcription factor (TFEB) significantly increases the number of these whorls.

Today we say goodbye to @ZhangTingxin, an outstanding postdoc and research scientist in our group, as he begins his independent lab at SUSTech (the first one from our lab!). He published our group’s first paper and has another under review. Congratulations and best of luck!!

The two knock-in mouse lines for myelinating oligodendrocytes are Mog-IRES-iCre (JAX#041041) and Mog-IRES-iCreERT2 (JAX#041042) with high efficient and specificity (no tamoxifen-independent recombination). If interested, please let JAX know so that they will not be cryopreserved.

Excited to introduce four new mouse lines described in our recent study @YiheZhang97 (soon available from JAX), including two lines for studying TFEB in broader contexts (TFEB 6xMyc, JAX#041044; Rosa26-TFEBS141A;S210A-Halo, JAX#041043) and two new KI lines for myelinating OLs.

Even more surprisingly, TFEB acts as a transcriptional repressor on these cholesterol genes, thereby reducing cholesterol levels when it is in the nucleus of myelinating oligodendrocytes.