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.

SUMMARY Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation we provide evidence that the pruritic phenotype in Bhlhb5 mutants may be due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritis and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.

Sensory experience is critical for the proper development and plasticity of the brain throughout life. Successful adaptation to the environment is necessary for the survival of an organism, and this process requires the translation of specific sensory stimuli into changes in the structure and function of relevant neural circuits. Sensory-evoked activity drives synaptic input onto neurons within these behavioral circuits, initiating membrane depolarization and calcium influx into the cytoplasm. Calcium signaling triggers the molecular mechanisms underlying neuronal adaptation, including the activity-dependent transcriptional programs that drive the synthesis of the effector molecules required for long-term changes in neuronal function. Insight into the signaling pathways between the synapse and the nucleus that translate specific stimuli into altered patterns of connectivity within a circuit provides clues as to how activity-dependent programs of gene expression are coordinated and how disruptions in this process may contribute to disorders of cognitive function.Keywords activity-dependent transcription; calcium; CREB; MEF2; MeCP2; Bdnf Experience Shapes the Nervous SystemDevelopment of the brain throughout life occurs in concert with exposure to the environment. The perturbation of sensory or psychosocial experience during early childhood may result in the impairment of cognitive function or behavior, as in cases of amblyopia due to congenital cataracts or intellectual impairment following early deprivation. Interventions that limit exposure to impoverished environments and promote exposure to enriched environments can prevent or even reverse the long-term consequences of deprivation on brain development (Maurer et al. 1999, Nelson et al. 2007. Why is early experience so important to cognition? During embryonic development of the central nervous system (CNS), genetically programmed molecular cues control the proliferation, migration, and maturation of neurons, leading to the widespread formation of connections between neurons and the establishment of rudimentary neuronal circuits. Although neuronal activity is not strictly required for the early development of synaptic connections (Verhage et al. 2000), spontaneous activity within the nascent circuits provides modulatory information about the appropriateness of the synapses formed (Katz & Correspondence to: Michael E. Greenberg, Michael.Greenberg@childrens.harvard.edu. Disclosure Statement: The authors are not aware of any biases that might be perceived as affecting the objectivity of this review. NIH Public Access Author ManuscriptAnnu Rev Cell Dev Biol. Author manuscript; available in PMC 2009 July 14. Published in final edited form as:Annu Rev Cell Dev Biol. 2008 ; 24: 183-209. doi:10.1146/annurev.cellbio.24.110707.175235. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Shatz 1996). As the CNS starts to receive and interpret environmental stimuli, sensory cues begin to drive synaptic activity. The discovery that blocking visu...

SUMMARY Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling.

Mutations in the MECP2 gene cause the autism spectrum disorder Rett Syndrome (RTT). One of the most common mutations associated with RTT occurs at MeCP2 Threonine 158 converting it to Methionine (T158M) or Alanine (T158A). To understand the role of T158 mutation in the pathogenesis of RTT, we generated knockin mice recapitulating MeCP2 T158A mutation. Here we show a causal role for T158A mutation in the development of RTT-like phenotypes including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those in Mecp2-null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. Importantly, the age-dependent development of event-related neuronal responses are disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials may serve as a biomarker for RTT and treatment evaluation.

CRE-binding protein (CREB) belongs to a family of transcription factors that mediates stimulus-dependent gene expression in neuronal and non-neuronal cells. Here we show that CREB is phosphorylated on its transcriptional regulatory site, Ser-133, in vivo in a neurotrophin-dependent manner. In mice harboring a null mutation in the Creb gene, sensory neurons exhibit excess apoptosis and degeneration, and display impaired axonal growth and projections. Interestingly, excess apoptosis is not observed in the central nervous system. CREB is required within sensory and sympathetic neurons for survival and axon extension since both of these neurotrophin-dependent processes are compromised in cultured neurons from CREB null mice. Thus, during their period of neurotrophin dependency, peripheral neurons require CREB-mediated gene expression for both survival and growth in vivo.

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SUMMARY Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here we report that the Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as a target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neuronal development to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural development in part through the precise regulation of Cadherin-11.