Sex differences in Mecp2-mutant Rett syndrome model mice and the impact of cellular mosaicism in phenotype development

Abstract

There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. Because MECP2 is subjected to X-inactivation, most affected individuals are female heterozygotes who display cellular mosaicism for normal and mutant MECP2. Males who are hemizygous for mutant MECP2 are more severely affected than heterozygous females and rarely survive. Mecp2 loss-of-function is less severe in mice, however, and male hemizygous null mice not only survive until adulthood, they have been the most commonly studied model system. Although heterozygous female mice better recapitulate human RTT, they have not been as thoroughly characterized. This is likely because of the added experimental challenges that they present, including delayed and more variable phenotypic progression and cellular mosaicism due to X-inactivation. In this review, we compare phenotypes of Mecp2 heterozygous female mice and male hemizygous null mouse models. Further, we discuss the complexities that arise from the many cell-type and tissue-type specific roles of MeCP2, as well as the combination of cell-autonomous and non-cell-autonomous disruptions that result from Mecp2 loss-of-function. This is of particular importance in the context of the female heterozygous brain, composed of a mixture of MeCP2+ and MeCP2- cells, the ratio of which can alter RTT phenotypes in the case of skewed X-inactivation. The goal of this review is to provide a clearer understanding of the pathophysiological differences between the mouse models, which is an essential consideration in the design of future pre-clinical studies.

Keywords: Epigenetics; MeCP2; Rett syndrome; Sex differences; X-chromosome inactivation.

Figure 1:. Skewed X-Chromosome Inactivation alters RTT phenotypes in Mecp2 heterozygous female brain.

The female Het brain is a mosaic of cells expressing the wildtype allele (MeCP2+) and those expressing the mutant or null allele (MeCP2−). Although a 1:1 ratio of MeCP2+ and MeCP2− cells is the norm (top), skewed X-chromosome inactivation (XCI) can lead to an increase in the relative percentage of either the MeCP2+ cells (bottom left) or the MeCP2− cells (bottom right). This change in the overall cellular environment alters specific phenotypes of both MeCP2+ and MeCP2− neurons, through non-cell-autonomous mechanisms. For both MeCP2+ and MeCP2− neurons, the direction of phenotypic change (arrows) is depicted relative to the same cell type under balanced (1:1) XCI. Magenta indicates expression of wildtype allele and cyan indicates expression of null allele.

Figure 2:. Neurons display both cell-autonomous and cell-non-autonomous disruptions in the female heterozygous brain.

Mecp2-mutant neurons in the brains of both female Hets and male nulls display aberrant size and morphology phenotypes. MeCP2− neurons in a Het brain display distinct morphologies from MeCP2+ neurons; however, they are not as severely disrupted as MeCP2− neurons in a null brain. In addition, MeCP2+ neurons in a Het brain are distinct from MeCP2+ neurons in a wildtype (WT) brain, for example, displaying decreased soma size and dendritic spine density. Other phenotypes, such as dendritic branching and morphology, are dependent only on MeCP2 expression within that neuron. Thus, specific phenotypes respond differently to the cellular environment, indicating that they are controlled by distinct cell-autonomous and cell-non-autonomous mechanisms. Arrows denote phenotypic change relative to MeCP2+ in a WT brain, dash indicates no change.