Nov 2, 2018

A brain network basis of Fragile X syndrome behavioral penetrance determined by X chromosome inactivation in female mice

BioRxiv : the Preprint Server for Biology
Eric SzelenyiPavel Osten


X-chromosome inactivation (XCI) in females is vital for normal brain function and cognition, as many X-linked genetic mutations lead to mental retardation and autism spectrum disorders, such as the fragile X syndrome (FXS). However, the degree by which XCI regulates disease presentation has been poorly investigated. To study this regulation in the mouse, here we quantified the brainwide composition of active-XC cells at single cell resolution using an X-linked MECP2-EGFP allele with known parent-of-origin. We present evidence that whole-brains, including all regions, on average favor maternal XC-active cells by 20%, or 8 million cells. This bias was conserved in heterozygous FXS mutant mice, which also corresponded to disease penetrance in maternal but not paternal FMR1 null mice. To localize the physical source of behavioral penetrance, brain-wide correlational screens successfully mapped mouse performance to cell densities in putative sensorimotor (e.g. sensory hindbrain, thalamus, globus pallidus) and sociability (e.g. visual/entorhinal cortices, bed nucleus stria terminalis, medial preoptic area) behavioral circuits of the open field sensorimotor and 3-chamber sociability assays, respectively. Overall, 50%/50% healthy/mutan...Continue Reading

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Mentioned in this Paper

MECP2 wt Allele
Fragile X Syndrome
Globus Pallidus
Methyl-CpG-Binding Protein 2
Regulation of Biological Process
FMR1 protein, human

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