Cell-specific expression of wild-type MeCP2 in mouse models of Rett syndrome yields insight about pathogenesis

Abstract

Rett syndrome (RTT), a leading cause of mental retardation with autistic features in females, is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). RTT is characterized by a diverse set of neurological features that includes cognitive, motor, behavioral and autonomic disturbances. The diverse features suggest that specific neurons contribute to particular phenotypes and raise the question whether restoring MeCP2 function in a cell-specific manner will rescue some of the phenotypes seen in RTT. To address this, we generated transgenic mice expressing inducible MeCP2 under the control of the brain-specific promoters calcium/calmodulin-dependent protein kinase II (CamKII) or neuron-specific enolase (Eno2) and bred them onto mouse models lacking functional MeCP2. Expression of normal MeCP2 in either CamKII or Eno2 distribution was unable to prevent the appearance of most of the phenotypes of the RTT mouse models. These results suggest that most RTT phenotypes are caused either by disruption of complex neural networks involving neurons throughout the brain or by disruption of the function of specific neurons outside of the broad CamKII or Eno2 distribution.

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

“…We have previously reported that transgenic mice expressing MeCP2-e2 under the NSE or CamKIIa promoters, when crossed to Mecp2 À/y elicited no significant behavioral or lifespan improvements. 27 Contrasting this previous study with the current data, in which we observe significant phenotypic prevention with widespread brain expression of MeCP2-e2, suggests that not only level, but also location of expression is important for MeCP2's overall activity in brain function. In addition, the expression of transgenic MeCP2 in glial cells in the transgenic mice described in this report could contribute to the behavioral amelioration and might explain the different results observed.…”

Atlas of transgenic Tet-Off Ca2+/calmodulin-dependent protein kinase II and prion protein promoter activity in the mouse brain

“…White matter regions were generally void of labeling, while the cerebral cortical layers and a number of subcortical regions demonstrated quite a substantial level of labeling. In accordance with previous reports (Bukalo et al, 2004;Chen et al, 1998;Mayford et al, 1996;Michalon et al, 2005;Alvarez-Saavedra et al, 2007), our examination of location and morphological characteristics of labeled cells gives the distinct impression that X-gal labeling is confined primarily to neurons (Fig. 4), with no association to glia.…”

“…The PrP promoter line has been successfully used in several studies of various diseases, including prion diseases (Safar et al, 2005;Tremblay et al, 1998), Parkinson's disease (Nuber et al, 2008), analysis of alcohol consumption (Choi et al, 2002), spinocerebellar ataxia type 3 (Boy et al, 2009), and neurofilament transport (Millecamps et al, 2007). The CamKII promoter line has been used for the investigation of synaptic plasticity, learning and memory consolidation (Bukalo et al, 2004;Limback-Stokin et al, 2004;Mayford et al, 1997;Wood et al, 2005), neurodevelopmental disorders (Alvarez-Saavedra et al, 2007;Jerecic et al, 2001), and for the generation of transgenic mouse models for Alzheimer's disease (Jankowsky et al, 2005), Huntington's disease (Yamamoto et al, 2000), Parkinson's disease (Nuber et al, 2008), neocortical degeneration (Muyllaert et al, 2008), schizophrenia (Pletnikov et al, 2008), and neurofibromatosis (Saito et al, 2007).…”

“…CamKII is known as a forebrain specific promoter while the PrP promoter activity is mainly distributed in the brainstem and cerebellum (Bailly et al, 2004;Boy et al, 2006;Bukalo et al, 2004;Chen et al, 1998;Ghavami et al, 1999;Liang et al, 1996;Liu et al, 2001;Mantamadiotis et al, 2002;Mayford et al, 1995Mayford et al, , 1996Tremblay et al, 1998;Alvarez-Saavedra et al, 2007;Yamamoto et al, 2000). At the cellular level, CamKII promoter activity is neuron specific and has not been reported in glia (Bukalo et al, 2004;Chen et al, 1998;Mayford et al, 1996Mayford et al, , 1997Michalon et al, 2005;Alvarez-Saavedra et al, 2007), whereas PrP promoter activity is seen in both neuronal and glia cell populations (Boy et al, 2006(Boy et al, , 2009Gotz et al, 2001). Using double-transgenic mice with the LacZ reporter gene (encoding the enzymatically detectable β-galactosidase) as a responder, we have performed comprehensive brain-wide mapping of promoter activity at the level of regions and cells in PrP/ LacZ (Boy et al, 2006) and CamKII/LacZ mice (present study).…”

Novel molecular players of X chromosome inactivation: new technologies and new insights

“…One such example is Rett syndrome, which is a rare neurodevelopmental disease caused by loss-of-function mutations in the X-linked gene MECP2 encoding Methyl CpG binding protein. As discussed above, reactivating Xi-linked MECP2 in Rett syndrome patients can restore symptoms associated with the disease and possibly reverse the disease [74][75][76] . But the lack of understanding of XCI has limited its applicability as a target for treatment.…”