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X-Inactivation01:58

X-Inactivation

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The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
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A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
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Behavioral characterization of system xc- mutant mice.

Elizabeth A McCullagh1, David E Featherstone1

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The slc7a11 gene, encoding xCT, impacts brain function. Mutant mice showed varied behavioral and chemical changes, but definitive links to system xc- loss remain unclear.

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Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • The slc7a11 gene encodes xCT, a key part of the system xc- amino acid transporter.
  • System xc- plays a role in importing cystine and exporting glutamate, particularly in the brain.
  • The precise function of slc7a11 and system xc- in the brain is not fully understood.

Purpose of the Study:

  • To investigate the in vivo function of slc7a11 and its protein product xCT in the mouse brain.
  • To characterize behavioral and neurochemical phenotypes of slc7a11 null mutant mice.
  • To determine if observed differences in mutant strains are attributable to the loss of system xc- function.

Main Methods:

  • Generation and behavioral testing of homozygous slc7a11 mutant mice (sut and xCT strains) and heteroallelic (xCT/sut) offspring.
  • Assessment of motor coordination and balance using rotarod tests.
  • Measurement of whole brain xCT protein levels via immunoblotting to confirm null alleles.
  • Microdialysis to measure interstitial glutamate levels in the striatum and cerebellum.

Main Results:

  • Homozygous sut mutant males exhibited reduced spontaneous alternation and open field movement; xCT and xCT/sut strains did not.
  • No significant differences were observed in rotarod tests across any mutant strains.
  • Immunoblotting confirmed the absence of xCT protein in all homozygous and heteroallelic mutant strains, validating them as null alleles.
  • Reduced striatal glutamate was observed in sut mutants but not in xCT or xCT/sut mutants.
  • No changes in EAAT-1, -2, or -3 expression were detected in whole brain homogenates.

Conclusions:

  • Distinct behavioral and neurochemical phenotypes exist between different slc7a11 mutant mouse strains.
  • The precise contribution of system xc- to these observed phenotypes requires further investigation.
  • The study highlights strain-specific effects and challenges in definitively linking observed changes to the loss of system xc- function.