Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome

Abstract

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity prior to death between 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.

Rett Syndrome and MeCP2

“…Further supporting the concept of MeCP2 isoformspecific functions, MeCP2E2 has been shown to interact with FOXG1, mutations of which are associated with RTT (Philippe et al 2010). In comparison, MeCP2E1 isoform interacts with YB-1, Matrin 3 and SFPQ proteins in human neuronal cell-line SH-SY5Y (Yasui et al 2014). Moreover, a MeCP2E1-specific phosphorylation site (S10) has been reported (Trinidad et al 2008) and RettBASE mutation database shows that MECP2 frame-shift/ deletion mutations (Table 2) can cause alterations in this phosphorylation site (p.S10RfsX45 and p.S10fs).…”

“…The examples of such null MeCP2 mouse models include Mecp2 tm1.1Bird , Mecp2 Jae and Mecp2 neoTam which demonstrate many RTT phenotypes (Guy et al 2001;Chen et al 2001;Pelka et al 2006). Moreover, a mouse model lacking MeCP2E1 expression recapitulated RTT-like phenotypes (Yasui et al 2014), in comparison with Mecp2e2-knockout model which lacked neurological phenotypes (Itoh et al 2012). Similarly, the mouse models harboring known RTT-causing MECP2 mutations have been helpful in determining the role of these mutations in RTT pathology.…”

Clinical and biological progress over 50 years in Rett syndrome

“…39 62 The two known protein isoforms of MeCP2 differ only at the extreme amino terminus and, despite some evidence for isoform specific-functions, 63 the two forms are considered to be largely functionally equivalent 53,64 although MeCP2 e1 is the dominant brain isoform. The original discovery of MeCP2 was a result of a biochemical screen for factors interacting with DNA and in particular with methylated cytosines (within the context of CpG sequences).…”

Modeling tics in rodents: Conceptual challenges and paths forward

“…However, not every repetitive movement is representative of a tic. Repetitive movements, such as elevated grooming (Kalueff et al, 2016), have been described as recapitulating tics (Xu et al, 2015a; Xu et al, 2015b; Xu et al, 2016); but dysregulated grooming has also been argued to recapitulate obsessive-compulsive symptoms (Ahmari et al, 2013; Greer and Capecchi, 2002; Shmelkov et al, 2010; Welch et al, 2007), trichotillomania (Feusner et al, 2009), autistic stereotypies (Peca et al, 2011; Zhou et al, 2016), Rett syndrome (Yasui et al, 2014), psychostimulant-related behavior (Berridge et al, 2005), and other clinical conditions (Kalueff et al, 2016). Given the evolutionary divergence between rodents and humans, it is unlikely that homologs of tics in mice will fully recapitulate all clinical characteristics of tics.…”