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FROM PARASITE TO PARTNER: A DOMESTICATED RETROTRANSPOSON DRIVING MYELINATION AND VERTEBRATE EVOLUTION




Myelination, a process by which an axon is wrapped around a myelin sheath, has had a crucial impact on vertebrates' evolution. It has provided saltatory conduction, i.e., increasing nerve impulses, which allows the signal to pass longer distances and paves the way to assist local metabolic support. This led to vertebrates attaining large body sizes and diversity within the species, which would not have happened without myelination. Myelination has allowed rapid conduction of signals without increasing axonal diameter, which has facilitated the number of axons to be packed, necessary for the evolution of the complex central nervous system (CNS). 

Moreover, it has been found that phylogenetically, compact myelin and genes related to it, like myelin basic protein (Mbp), started to emerge concurrently with jaws in vertebrates. Myelin has been found in the earliest living vertebrate, Chondrichthyes (cartilaginous fish); however, not been found in Agnatha (jawless fish), signifying that it emerged when the divergence of jawless vertebrates occurred, which is a crucial evolution. Phylogenetic analysis of 22 species proved that the myelin sheath is acquired after speciation (vertebrates and invertebrates) and then diversifies in each species. 


Phylogenetic relationship of RNLTR12-int and Mbp


However, despite the function associated with myelination, we haven't found out the molecular basis of why and how these events are triggered within vertebrate evolution. This long-time mystery has been solved and published in Cell Press titled “A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression” where the authors have found that RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination, which has been shown to regulate Mbp.

Endogenous retrovirus (ERV) type of retrotransposons are ancient viral sequences that have been present in the eukaryotic genome for millions of years. These retrotransposons are mobile genetic elements that move through an RNA intermediate. Even though most of them have lost their transposition capability due to the accumulation of mutations, some have been domesticated, i.e, they incorporate into the host genome and begin to perform functions that benefit the host. Despite our knowledge of their role in stem cell identity, there is no knowledge of their role in gene networks during the oligodendrocyte (OLs, cells that produce myelin sheath) maturation, formation of myelinating OLs.

Through a meta-analysis of microarray-based gene expression data using retrotransposon-specific probes in oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) isolated from postnatal day 7 rat brains, differentially expressed retrotransposons were identified. They found a co-expression of a particular retrotransposon called RNLTR12-int, which showed relatively higher expression in OLs than OPCs. Through RT-qPCR, it was found that RNLTR12-int is expressed 2.5-fold higher in OL than in OPC. Further, it was found that RNLTR12-int has a consensus sequence of ERV1, i.e, it is a part of the ERV1 retrotransposon but still has parts of the Gag-Pol open reading frames which are required for the replication. However, rather than producing proteins, they are serving as a long non-coding RNA (lncRNA). 

When the authors knocked out the RNLTR12-int, they found that OPCs couldn't turn into OLs. Moreover, the reduction of the Mbps in the OLs was 98% when compared with the control. Through RT-qPCR, it was found that Mbp mRNA levels were drastically reduced, and the Cnp (early differentiation marker of OPCs to OL) was also drastically reduced, implying that Mbp transcription is affected due to inhibition of mRNLTR12-int and mRNLTR12-int has an role in the differentiation of the cells to undergo maturation (from OPCs to OL)). 

Further, they also proved that RNLTR12-int is also crucial in the peripheral nervous system (PNS) as CNS. In PNS, myelin sheaths are generated by Schwann cells (SCs) and myelin protein zero (MPZ) and Mbp, both are important for myelin formation. When RNLTR12-int was knocked out, both MPZ and Mbp expression were decreased, indicating they also regulate the transcriptional regulation of these proteins. So they named RNLTR12-int as RetroMyelin.


SOX10-mediated transcription of Mbp is RNLTR12-int transcript-dependent


SRY-box transcription factor 10 (SOX10) is an already known transcriptional activator of Mbp. Through RNA immunoprecipitation using the SOX10 antibody, they found that SOX10 binds to the lncRNA of RetroMyelin. SOX10 binds to the S1 and S2 regions of the Mbp promoter; however, when RetroMyelin was knocked out, SOX10 couldn't bind to the S1 and S2 regions. By this, they found that RetroMyelin lncRNA binds to SOX10, and binding of this lncRNA to the transcriptional factor is essential for proper binding of SOX10.


Graphical representation of the transcriptional regulation of Mbp by RetroMyelin (RNLTR12-int)


In conclusion, for the maturation or differentiation of OPCs into OLs, expression of RetroMyelin is crucial as they bind to SOX10 and initiate the binding of SOX10 to the promoter of Mbp. Thus, RetroMyelin was domesticated or co-opted to regulate the transcription of Mbp, which is profoundly needed for myelination, and has allowed vertebrates to evolve over the years. 


REFERENCE

Ghosh, T., Almeida, R. G., Zhao, C., Mannioui, A., Martin, E., Fleet, A., Chen, C. Z., Assinck, P., Ellams, S., Gonzalez, G. A., Graham, S. C., Rowitch, D. H., Stott, K., Adams, I., Zalc, B., Goldman, N., Lyons, D. A., & Franklin, R. J. M. (2024). A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression. Cell, 187(4), 814–830.e23. https://doi.org/10.1016/j.cell.2024.01.011

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