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THE IMPACT OF RETROTRANSPOSONS ON MYELIN EVOLUTION: A FOCUS ON RNLTR12-INT AND MBP REGULATION


Myelination is a process that has a significant role in vertebrate evolution, which is the formation of the myelin sheath that surrounds the axon. This myelination has allowed the axon to acquire saltatory conduction (i.e.) electric signal or action potential jumping between the gaps of the myelin sheath, commonly known as nodes of Ranvier. Moreover, this myelination also led to a more complex brain and morphological diversity due to the unnecessity of increasing axonal diameter for rapid conduction which is necessary for the evolution of the complex central nervous system (CNS). On analyzing it was also identified that the phylogenetically, system with myelin, genes coding for them, and myelin basic proteins (Mbp) have been found in living vertebrates in ancient beings like Chondrichthyes (cartilaginous fish), however not in Agnatha (jawless fish) signifying that they got evolved in jawed vertebrates. Even though myelination has a bigger advantage to the significant function of CNS, the molecular explanation of what stimuli or factors triggered this event is still a question mark. 


Now, we have an answer to this, a paper titled “A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression” published in Cell reported that RNA-level expression of RNLTR12-int, a retrotransposon is essential for this myelination.


Retrotransposons are mobile elements in the eukaryotic genome that shift from one place to another within the genome through an RNA intermediate. ERV, Endogenous retrovirus type retrotransposon are remains of ancient retroviral sequences that are integrated in the genome of the host’s germline cells, which over evolution becomes part of the host genome acting as gene regulators or individual genes. Here while analyzing gene networks associated with oligodendrocytes (glial cells in CNS that form myelin sheath), researchers identified that an expression of  RNLTR12-int, a retrotransposon originated from a retrovirus is crucial for Mbp expression. 


Production of myelin by oligodendrocytes is pivotal for axon conduction, normal physiology, and regeneration after demyelination. This myelin aids in rapid signal transmission, which is crucial for vertebrate evolution, significantly in predatory and escape behavior. In CNS, myelin basic protein is needed to pull adjacent membranes together like a zipper. However, Mbp is only found in jawed vertebrates which results in compact myelin, which has its own advantages like fast conduction and need for small axon diameter which is not found in invertebrates and jawless vertebrates. 


In the analysis, retroviral origin RNLTR12-int-like sequences (called RetroMyelin) are found in all jawed vertebrates where myelination is active. RetroMyelin also showed high similarity within individual species but not between species suggesting that they were formed due to independent retroviral invasions after the species diverge. Further investigating their relationship with Mbp, they found that RNLTR12-int or RetroMyelin expressed RNA binds to transcription factor SOX10, and this binding is key as SOX10 mediates transcription of Mbp. Even though the detailed mechanism is not explored, it is suggested that RetroMyelin encoded RNA acts as a transcriptional activator. 


However, the study also has some limitations; RetroMyelin sequences are repetitive sequences so they might have multiple copies, and their loci are not specific moreover it means that even if one copy got eliminated, others may express or take the place, so the sufficiency of RetroMyelin for Mbp regulation is still something that needs to be explored. 


In conclusion, they suggest that RetroMyelin was co-opted (transposable elements (TEs) that have been repurposed by hosts to regulate genome-wide changes in transcription and chromatin) to regulate the MBp transcription, so endogenization of ERV1 has coupled in the genome which led to crucial evolution in vertebrates. 


REFERENCE


Ghosh T, Almeida RG, Zhao C, Mannioui A, Martin E, Fleet A, et al. A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression. Cell. 2024;187(4):814-830.e23. doi:10.1016/j.cell.2024.01.011.


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