The yin and yang of MeCP2 phosphorylation

Abstract

Studies of the childhood neurological disorder Rett syndrome and methyl-CpG-binding protein 2 (MeCP2) taught us that MeCP2 performs a balancing act in modulating neurological functions. Rett syndrome, characterized by cognitive deficits, motor impairments, autistic-like features, seizures, and stereotyped repetitive hand movements is caused by loss of MeCP2 function (1). On the other hand, a syndrome with overlapping features including autism, mental retardation, seizures, motor impairments, and repetitive movements results from gain of MeCP2 function due to doubling or tripling the protein level (2–4). In animal models, neuronal loss of MeCP2 leads to reduced glutamatergic synaptic strength due to reduced synapse numbers and gain of MeCP2 in neurons results in increased synaptic strength due to increased synapse numbers (5). Until recently it was believed that MeCP2 was exclusively expressed in neurons in the central nervous system (6, 7), we now know MeCP2 is also expressed in astrocytes and that MeCP2 deficient astrocytes cannot support neuronal dendritic arborization (8). At the molecular level, several studies have shown that MeCP2 functions as a transcriptional repressor by binding to methylated CpG dinucleotides and recruiting co-repressor proteins to silence gene expression (9, 10). However, in vivo studies showed that loss of MeCP2 leads to reduced expression of thousands of genes suggesting that MeCP2 may be a transcriptional modulator important for decreasing the expression of some genes and enhancing the expression of others (11). In this issue of PNAS, we learn about yet other balancing forces in modulating MeCP2 function: the differential phosphorylation of MeCP2 in response to neuronal activity (12). Such phosphorylation events may be one key mechanism by which MeCP2 modulates gene expression. Fig. 1. MeCP2 phosphorylation: a balancing act in neurons. A. MeCP2 in resting neurons … 1To whom correspondence should be addressed. E-mail: hzoghbi{at}bcm.edu