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Visualizing X Chromosome Inactivation

Researchers develop mouse lines to help them see whether the maternal or paternal X chromosome is inactivated.

By | January 21, 2014

In one mouse's left and right retinas, cells that silenced the maternal X chromosome are red and those that silenced the paternal X chromosome are green.NATHANS LAB, COURTESY OF NEURONIn every female eutherian mammalian cell, one of the two X chromosomes is inactivated. Though visual representations of X inactivation are well known—the pattern of a calico cat’s fur, for instance—understanding of how X chromosome inactivation affects disease and development is still limited. Now, Jeremy Nathans of Johns Hopkins University School of Medicine and his colleagues have generated transgenic mice in which X chromosome inactivation can be visualized in individual cells. The work was published this month (January 8) in Neuron.

The researchers generated mouse lines with Cre-inducible, nuclear-localized fluorescent reporters—either green fluorescent protein (GFP) or tdTomato, a red fluorescent protein—inserted into the locus for the X-linked Hprt gene. Each mouse line used a tissue-specific promoter to drive Cre, and the red and green fluorescent lines were bred to generate heterozygous females containing one of each X chromosome. The team analyzed the green and red fluorescence in each cell in which Cre was expressed, and found that the patterns of X inactivation varied widely from tissue to tissue and sometimes showed distinct left-right asymmetry. Variable X inactivation led to differences in the manifestation of an X-linked disease that affects blood vessels in the retina and contributed to biological diversity in the central nervous system.

“Diversity in the brain is the name of the game,” Nathans told The New York Times. He said that having different patterns of gene expression could help the brain process information. In their paper, the authors suggested that the system could be used in a variety of ways, including for visualization of X inactivation as mice develop and for sorting and comparing cells in which an X chromosome with a mutation is active to cells with normal X chromosomes to evaluate differences in gene expression.

Scientists will continue to explore how X chromosome inactivation occurs and affects biological processes. Harvard Medical School’s Jeannie Lee, a professor of genetics and pathology who was not involved in the research, told the Times that “the knowledge of this is exploding.”

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