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early-life stress, Mecp2, HPA axis, epigenetic programming, Avp, Crh, Pomc
Abstract:
Mutations in the X-linked gene MECP2, the founding member of a family of
proteins recognizing and binding to methylated DNA, are the genetic
cause of a devastating neurodevelopmental disorder in humans, called
Rett syndrome. Available evidence suggests that MECP2 protein has a
critical role in activity-dependent neuronal plasticity and
transcription during brain development. Moreover, recent studies in mice
show that various posttranslational modifications, notably
phosphorylation, regulate Mecp2's functions in learning and memory, drug
addiction, depression-like behavior, and the response to antidepressant
treatment. The hypothalamic-pituitary-adrenal (HPA) axis drives the
stress response and its deregulation increases the risk for a variety of
mental disorders. Early-life stress (ELS) typically results in sustained
HPA-axis deregulation and is a major risk factor for stress related
diseases, in particular major depression. Interestingly, Mecp2 protein
has been shown to contribute to ELS-dependent epigenetic programming of
Crh, Avp, and Pomc, all of these genes enhance HPA-axis activity. Hereby
ELS regulates Mecp2 phosphorylation, DNA binding, and transcriptional
activities in a tissue-specific and temporospatial manner. Overall,
these findings suggest MECP2 proteins are so far underestimated and have
a more dynamic role in the mediation of the gene-environment dialog and
epigenetic programming of the neuroendocrine stress system in health and
disease.
