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Human Molecular Genetics Advance Access published online on May 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi191
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 24, 2005
Revised April 29, 2005
Accepted May 6, 2005

Article

Reduced proportion of Purkinje cells expressing paternally derived mutant Mecp2308 allele in female mouse cerebellum is not due to a skewed primary pattern of X-inactivation

Catherine M. Watson 1, Gregory Pelka 2, Tatiana Radziewic 1, Mona D. Shahbazian 3, John Christodoulou 4, Sarah L. Williamson 4, and Patrick P.L. Tam 5*

1 Embryology Unit, Children's Medical Research Institute, NSW, Australia
2 Embryology Unit, Children's Medical Research Institute, NSW, Australia; Discipline of Pediatrics and Child Health, University of Sydney, NSW, Australia; Western Sydney Genetics Program, Children's Hospital at Westmead, NSW, Australia
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston Texas 77030 U.S.A.
4 Discipline of Pediatrics and Child Health, University of Sydney, NSW, Australia; Western Sydney Genetics Program, Children's Hospital at Westmead, NSW, Australia
5 Embryology Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia

* To whom correspondence should be addressed.
Patrick P.L. Tam, E-mail: ptam{at}cmri.usyd.edu.au


  Abstract

Rett Syndrome (RTT) is an X-linked disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. The pattern of X-chromosome inactivation (XCI) is thought to play a role in phenotypic severity. In the present study, patterns of XCI were assessed by lacZ staining of embryos and adult brains of mice heterozygous for a X-linked Hmgcr-nls-lacZ transgene on a mutant mouse model of RTT. We found that there was no difference between the lacZ staining patterns in the brain of wild-type and heterozygous mutant embryos at embryonic day 9.5 (E9.5) suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wild-type mice when the mutant allele was inherited from the mother. However when the mutant allele was paternally inherited a significant difference was detected. Thus parental origin of the mutation may have a bearing on phenotype through XCI patterns. An estimation of the Purkinje cell precursor number based on X-inactivation mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in the wild-type mice. Therefore it is likely that the number of precursor cells allocated to the Purkinje cell lineage is affected by a paternally inherited mutation in Mecp2. We also observed that the pattern of XCI in cultured fibroblasts was significantly correlated with patterns in the Purkinje cells in mutant animals but not in wild-type mice.

Keywords: X-inactivation; Rett syndrome; methyl CpG-binding protein 2; epigenetics.
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