Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation

Abstract

Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT.

The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons

“…44 On the other hand, BDNF promoter IV binds the transcriptional repressor, MeCP2 (a methyl-CpG-binding domain protein), in complex with the corepressor sin3a and HDACs. [45][46][47] Inhibition of HDAC by VPA or other inhibitors could cause dissociation of the repressor-corepressor complex from the promoter, resulting in transcriptional disinhibition. It is noteworthy that the antidepressant effect of imipramine is largely reversed by HDAC5 overexpression in the hippocampus of mice subjected to chronic defeat stress, which per se induces downregulation of BDNF III and IV mRNA.…”

Advances in behavioral genetics: mouse models of autism

“…345 There are also reports that Mecp2 plays a role in the regulation of Bdnf levels. 134,201,202 Reduction in the levels of Bdnf exacerbates the phenotype of both the Rett syndrome-model mouse 346 and the Sert deletion line. [208][209][210] In the Rett syndrome-model mouse, Bdnf overexpression with an inducible Bdnf transgene leads to partial correction of abnormalities linked to loss of Mecp2 function.…”

“…One study demonstrated that Mecp2 regulation of dendritic patterning and other components of neuronal connectivity is dependent on phosphorylation induced by neuronal activation. 134 The application of a selective CaMKII inhibitor, but not inhibitors of other kinases (CaMKK, protein kinase A, protein kinase C, mitogen-activated protein kinase, cyclin-dependent kinase 5 (CDK5), or phosphatidylinositol 3-kinase (PI3K)), blocked the stimulation-dependent phosphorylation of Mecp2, suggesting that CaMKII modulates the state of Mecp2 activation during synaptic transmission. 134 In addition to altered translation, dysregulation of CaMKII could occur through processes involved in autophosphorylation.…”

“…134 The application of a selective CaMKII inhibitor, but not inhibitors of other kinases (CaMKK, protein kinase A, protein kinase C, mitogen-activated protein kinase, cyclin-dependent kinase 5 (CDK5), or phosphatidylinositol 3-kinase (PI3K)), blocked the stimulation-dependent phosphorylation of Mecp2, suggesting that CaMKII modulates the state of Mecp2 activation during synaptic transmission. 134 In addition to altered translation, dysregulation of CaMKII could occur through processes involved in autophosphorylation. Weeber et al 116 have reported that Ube3A (mÀ/p þ ) mice have higher levels of aCaMKII phosphorylation at a site inhibitory for enzymatic activity.…”

“…[192][193][194] Work with mouse lines characterized by deficient Bdnf has shown that these trophic effects are important for normal serotonergic neurotransmission. [195][196][197][198][199][200] In addition, several lines of evidence have provided support for a role of Mecp2 in the regulation of activity-dependent transcription of Bdnf, 134,201,202 suggesting that alterations in 5-HT signaling could arise from deficient Mecp2 function, through dysregulation of Bdnf. Bdnf-null mice die soon after birth, but mutants have been developed with conditional disruption of Bdnf, limited to either the prenatal or postnatal period.…”