15 - 07 - 2006: Ube3a expression is not altered in Mecp2 mutant mice

Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder characterized by cognitive regression, loss of purposeful hand movements and speech, stereotypies, ataxia, seizures, mental retardation and acquired microcephaly. Mutations in MECP2, encoding methyl-CpG-binding protein 2, are responsible for approximately 90% of classic RTT cases. RTT displays phenotypic overlap with Angelman syndrome, a disorder caused by loss of expression of the imprinted gene UBE3A. MeCP2 binds to methylated DNA and may alter the expression of imprinted genes, thereby suggesting a mechanistic link between the two disorders. Here, we tested the hypothesis that MeCP2 deficiency affects expression of Ube3a in mouse models of RTT. As Ube3a is only imprinted in brain, we evaluated Ube3a expression in brains of 15 different litters of neonatal or 8-week-old male Mecp2 mutant mice by real-time quantitative RT-PCR and western blot analysis. We found no significant differences between Mecp2(tm1.1Bird/Y) or Mecp2(tm1.1Jae/Y) mutants and their wild-type male siblings that served as negative controls. In positive control mice carrying a maternally inherited Ube3a deletion, Ube3a sense transcript and protein levels were drastically reduced. Our data contrast with two recent reports of substantially decreased Ube3a expression in brain tissues of MeCP2-deficient mice. We, therefore, challenge the conclusion that decreased UBE3A/Ube3a expression contributes to the pathophysiology of RTT.

Lay Summary
Rett syndrome and Angelman Syndrome are both autism-spectrum disorders, which share a number of clinical features. Similarly, mice with Mecp2 mutations (Rett syndrome mouse model) and mice with loss of Ube3A (Angelman syndrome mouse model) share similar behaviors, including movement disorders, seizures, learning disabilities, and shorter lifespan. With such similarities, examining whether a common molecular pathway leading to these symptoms exists is a worthwhile pursuit - namely, are Ube3A levels similarly altered in Rett syndrome. In fact, other researchers have previously reported such a relationship. However, a hallmark of scientific investigations is result reproducibility. In this paper, the authors use a more detailed investigative strategy to confirm the finding of altered Ube3A levels in the mouse model of Rett syndrome. However, contrary to the two previous reports, the authors find no change in the Ube3a levels in the same Rett mice previously studied. The authors go on to explain the limitations of the previous studies, and explain why they stand behind the results of this much more thorough investigation. Indeed, identifying and confirming the molecular pathways that are altered (or in this case, not altered) within the mouse model of Rett syndrome ultimately aid in a better understanding of this disease, and thus this paper is an important addition to Rett research.