RT Journal Article
SR Electronic
T1 MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.10.05.510925
DO 10.1101/2022.10.05.510925
A1 Sameer S. Bajikar
A1 Ashley G. Anderson
A1 Jian Zhou
A1 Mark A. Durham
A1 Alexander J. Trostle
A1 Ying-Wooi Wan
A1 Zhandong Liu
A1 Huda Y. Zoghbi
YR 2022
UL http://biorxiv.org/content/early/2022/10/06/2022.10.05.510925.abstract
AB Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 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 Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.Competing Interest StatementThe authors have declared no competing interest.