MeCP2 Protein Defects Led to RNA Errors in Brains of Rett Mice

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Impaired function of the MeCP2 protein — the most common cause of Rett syndrome — causes defects in a process called RNA splicing, affecting protein production from genes important for nerve cell communication.

The study with that finding, “Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models,” was published in the journal Nature Communications.

While the MeCP2 protein, derived from the MECP2 gene, is found in several tissues, it is highly abundant in the brain, where it regulates nerve cell function and communication. However, despite numerous studies, the molecular mechanism underlying Rett syndrome remains poorly understood.

MeCP2 is known to regulate gene activity via different processes, including by mediating splicing of immature messenger RNA (mRNA).

mRNA is the molecule that carries DNA information to the sites where proteins are produced. RNA splicing is a natural process in which immature RNA sequences are processed to generate a functional protein-coding sequence.

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In the brain, the RNA-binding fox-1 (Rbfox) family is known to play critical roles in splicing regulation, as when it associates with other proteins in a complex called large assembly of splicing regulators (LASR). But even though it has been shown to contribute to neurological disorders in the brain, the Rbfox protein family has yet to be associated with Rett.

To better understand how MeCP2 may regulate gene expression (activity), researchers in China conducted lab (in vitro) tests to assess the protein’s interacting partners.

Results showed that the Rbfox family interacts with MeCP2, supporting this key Rett protein as a new “subunit of the previously identified RBFOX2/LASR complex,” the researchers wrote.

Further experiments confirmed that MeCP2 directly interacts with RBFOX2, a key member of the Rbfox/LASR complex. The researchers observed that MeCP2 acts as a bridge between methylated DNA (a chemical mark that regulates gene activity) and the Rbfox/LASR complex on its immature mRNA targets.

In human and mouse cells, deletion of MeCP2 led to the dissociation of the RBFOX2/LASR complex, which resulted in impaired binding of the complex to its targets and to dysfunctions in RNA splicing. Among such targets are genes involved in synapses, the junctions between two nerve cells that allow them to communicate.

The complex was disrupted in mice genetically engineered to lack their form of the MECP2 gene or carrying one of the most common mutations seen in Rett patients, called T158M.

The scientists further investigated why MeCP2 is essential for the formation of MeCP2/Rbfox/LASR complex. They found that MeCP2 aggregates with Rbfox proteins, forming liquid condensates located in the cell’s nucleus. This was seen in lab-grown cells, but also in the cerebral cortex of mice, a brain region responsible for complex cognitive functions. Deletion of MeCP2 or mice carrying the T158M mutation showed defects in the nuclear condensates with Rbfox proteins.

Overall, “these results reveal a mechanism that may underlie RTT [Rett] pathogenesis [disease] where MeCP2 functions in splicing control through driving the assembly of the Rbfox/LASR complex,” the study concluded.