Monday, 23 February 2015

Producing oligodendrocytes with SOX

Elevated In Vivo Levels of a Single Transcription Factor Directly Convert Satellite Glia into Oligodendrocyte-like Cells.,Weider M, Wegener A, Schmitt C, Küspert M, Hillgärtner S, Bösl MR, Hermans-Borgmeyer I, Nait-Oumesmar B, Wegner M. PLoS Genet. 2015;11(2):e1005008. 

Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.

SOX10 has nothing to do with Socks but it is a factor that turns the production of other proteins on. This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of what a stem cell will be come. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a shuttle protein in the nucleus and is important for neural development. Mutations in this gene are associated withWaardenburg-Shah and Waardenburg-Hirschsprung disease.
Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix transcription factor encoded by theOlig2 gene. The protein is of 329 amino acids in length, 32kDa in size and contains 1 basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in CNS, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining motor neuron and oligodendrocyte differentiation, as well as its role in sustaining replication in early development.

Yet more information on myelination and yet more ways to do it

3 comments:

  1. Sounds promising, let's do it..........oh wait, it's just another research article, sorry my fault. Seriously, I don't think people realize the number of transcription factors that determines gene activation. Unfortunately to activate silenced OPCs, in other words, to go back in human development, neural progenitor cells will have to recapitulate the process of myelination in the developing infant (i.e. re-establish synapses, maintain a homeostatic ion balance derived from mitochondrial activity). Obviously in the adult CNS the myelin/axon repair pathway is an evolutionary "dead end". It would seem that such a complex CNS would have more redundancy built in to ensure survival. One injury to the CNS and you're out of luck.

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    1. So are you saying maybe we should concentrate in stopping the damage occurring in the first place?

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    2. Yeah, hit early and hard with potent immunosuppressives and use myeloablative SCs to promote repair ASAP. Restore the CNS environment to what it was before the insult occurred thereby preventing smoldering inflammation and subsequent neurodegeneration. As team G states "time is brain" be aggressive instead of wait and see approach with DMTs.

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