MeCP2 regulates <i>Gdf11</i>, a dosage-sensitive gene critical for neurological function.

Abstract

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and <i>MECP2</i> duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (<i>Gdf11</i>). <i>Gdf11</i> is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing <i>Gdf11</i> dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of <i>Gdf11</i> alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of <i>Gdf11</i> decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that <i>Gdf11</i> dosage is important for brain function.