MECP2 disorders: from the clinic to mice and back
Laura Marie Lombardi, … , Steven Andrew Baker, Huda Yahya Zoghbi
Laura Marie Lombardi, … , Steven Andrew Baker, Huda Yahya Zoghbi
Published August 3, 2015
Citation Information: J Clin Invest. 2015;125(8):2914-2923. https://doi.org/10.1172/JCI78167.
View: Text | PDF
Review

MECP2 disorders: from the clinic to mice and back

Abstract

Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies.

Authors

Laura Marie Lombardi, Steven Andrew Baker, Huda Yahya Zoghbi

×

Figure 2

Functional modes of MeCP2.

Options: View larger image (or click on image) Download as PowerPoint
Functional modes of MeCP2. (A) One critical activity of MeCP2 is the bin...
(A) One critical activity of MeCP2 is the binding of methylated cytosines through its MBD (blue). Once it binds DNA, MeCP2 may function by altering the chromatin structure. Left: AT-hooks are able to change the conformation of DNA. The presence of three AT-hooks in MeCP2 suggests that MeCP2 may be able to bend DNA like the HMGA proteins with which MeCP2 exhibits homology. In this scenario, the primary targeting of MeCP2 via the MBD would then allow the flexible C-terminus of the protein (purple) to engage proximal DNA via its positively charged AT-hooks. Right: The fundamental unit of chromatin is the nucleosome, a histone octamer wrapped in 1.65 turns of DNA (red). The DNA between nucleosomes is called linker DNA. Linker histone H1 (yellow) and MeCP2 share a common nucleosomal binding site, the linker DNA entry/exit position. MeCP2 is able to compete off histone H1 in vitro, like HMGA proteins, and neurons lacking MeCP2 display increased H1. H1 plays a critical role in establishing higher-order chromatin, suggesting that antagonism by MeCP2 affects chromatin architecture. (B) MeCP2 may alter transcription by recruiting effector proteins. MeCP2 is able to repress methylated reporters in vitro when its TRD is intact. Thus, the TRD (within the flexible, basic C-terminus [purple]) may function as a bridge between MBD (blue) targeting and transcriptional effectors. Recently, it was discovered that Rett patient mutation R306C (edge of the TRD) disrupts interaction of MeCP2 with the NCoR/SMRT corepressor complex.