Female mice exhibit a more pronounced cognitive decline when only one of their two X chromosomes is active: the one inherited from their mother. This finding was published on January 22 in the journal Nature. Edith Heard, a professor at the Collège de France and specialist in epigenetics and X chromosome inactivation, described the results as "exciting."
Female mammals possess two X chromosomes in their cells, one inherited from each parent. Males have one X chromosome from their mother and a Y chromosome from their father. If both X chromosomes were active in females, the cells would not be viable. An evolutionary process has established a mechanism to inactivate one of the two X chromosomes in each female cell early in embryonic development, which is an epigenetic process involving the addition of chemical marks to DNA.
Typically, this process is random. As a result, in half of the female cells, the maternal X is inactivated, while in the other half, the paternal X is inactivated. However, there can be a "bias in X inactivation." A 2006 American study found that while the majority of women had random X inactivation, a minority exhibited significant asymmetry, with 95% of cells having the paternal X inactivated.
Another notable observation involves women with Turner syndrome, characterized by a single X chromosome. Claire Rougeulle, director of the research center at the Curie Institute in Paris, noted that these women exhibit cognitive differences depending on whether they inherit the maternal or paternal X.
In the January 22 study, researchers from the University of California, San Francisco, created female mice where only the maternal X chromosome was active. They achieved this by inactivating a gene, XIST, in the maternal X chromosome, which triggers X inactivation. They compared these mice to normal counterparts where X inactivation is random.
The results indicated that female mice with only the active maternal X exhibited reduced memory and learning abilities as they aged. In their hippocampus, a crucial brain structure for learning and memory, the active maternal X accelerated the biological aging of neurons.
However, no other bodily functions were affected. The cardiac function, bone density, energy metabolism, blood sugar levels, and body fat percentage in these mice were identical to those of normal mice of the same age.
Claire Rougeulle explained that the X chromosome carries numerous genes essential for basic cellular functions, as well as immune and cognitive functions. Eric Gilson, a specialist in aging at the University Côte d'Azur, highlighted the role of certain immune genes identified in the study. Researchers found nine genes completely silenced on the maternal X chromosomes but not on the paternal X chromosomes. They used CRISPR gene-editing technology to "turn on" these three immune-related genes, resulting in a significant recovery of cognitive functions in the affected female mice.
Edith Heard noted the significance of the maternal X's influence on cognitive behavior, stating that the active maternal X is consistently present in all males. This raises questions about whether females who randomly activate more of their maternal X may experience greater cognitive disorders with age.
These findings suggest that the parental origin of an X chromosome can significantly impact brain health, prompting further investigation into the cognitive effects related to X chromosome inactivation.