MeCP2 Forms Protein Complex to Help Regulate Brain Health, Study Says

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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MeCP2 protein | Rett Syndrome News | illustration of scientist in lab

The protein MeCP2 normally forms a complex with several other proteins in the brain that helps to regulate the development of connections between brain cells, a study reported.

These findings offer new insight into how Rett syndrome and other conditions caused by mutations affecting MECP2 can develop.

The study “Disruption of MeCP2–TCF20 complex underlies distinct neurodevelopmental disorders” was published in the journal PNAS.

Rett syndrome is mostly caused by mutations in a gene called MECP2, which contains instructions for making the MeCP2 protein. A disorder called MECP2 duplication syndrome (MDS), characterized by moderate to severe intellectual disability almost exclusively in males, is linked to abnormally high MeCP2 activity.

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The MeCP2 protein is known to associate with DNA in cells, particularly brain cells, and is thought to help regulate how genes are “turned on or off.” However, the detailed molecular mechanisms of how the MeCP2 protein normally functions — and how these functions are impaired in disease states — remains poorly understood.

An international team led by scientists in Texas conducted a series of biochemical experiments showing that, within brain cells, the MeCP2 protein forms a complex with several other proteins, including TCF20 and PHF14. Notably, in cells engineered to lack PHF14, MECP2 and TCF20 could no longer form this complex.

“These data indicate that MeCP2 binds TCF20 though PHF14 to form a stable complex,” the scientists wrote.

Further cell experiments showed that Rett-causing mutations in the MeCP2 protein could interfere with the protein’s ability to interact with PHF14 and enter the TCF20 complex.

Analyses of mouse brain cells indicated that cells with more activity in the Mecp2 gene (the mouse form of MECP2) also tended to also have increased activity in genes that code for TCF20 and other components of the complex.

Work in mouse neurons (nerve cells) showed that reducing levels of TCF20 lowered levels of BDNF, a signaling molecule known to help promote synapse formation (connections between cells).

Based on these data and what’s already known about the proteins, the researchers suspect that TCF20 and MeCP2 work together to regulate the activity of  genes that code for BDNF, which controls levels of this signaling molecule and ultimately regulates synapse formation.

Further supporting the idea of co-regulation between these proteins, the researchers found that lowering TCF20 levels could normalize synapse formation in cell models where the MECP2 gene is overactive.

To understand more about the TCF20 protein’s role, the researchers created mice that expressed a lower-than-normal amount of this protein (completely abolishing TCF20 led mice to die shortly after birth). Through a battery of behavioral tests, they illustrated that these TCF20-deficient mice exhibited characteristics typically seen in mouse models of Rett syndrome — for example, an abnormal lack of anxiety responses, and memory and learning deficits.

“The partial overlap of neurobehavioral deficits between the two mouse models suggests that TCF20 and MeCP2 share common downstream neuronal pathways,” the scientists wrote. Analyses of brain genetic data showed that there were indeed similar changes in gene expression (how genes are “read”) in TCF20-deficient and MeCP2-mutant mice.

In other experiments, the researchers showed that lowering TCF20 levels could normalize some behaviors in a mouse model of MDS (characterized by abnormally high MECP2 activity).

The scientists then conducted analyses of human genetic and clinical data, and found two patients with Rett-like disease with mutations in the gene that codes for PHF14. Molecular tests indicated that these mutations disrupted PHF14’s ability to mediate the connection between TCF20 and MeCP2.

“These human genetic and biochemical data raise the possibility that disruption of MeCP2–PHF14–TCF20 interaction could impair normal brain development,” the researchers wrote.