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MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function

Sameer S. Bajikar, Ashley G. Anderson, Jian Zhou, Mark A. Durham, Alexander J. Trostle, Ying-Wooi Wan, View ORCID ProfileZhandong Liu, View ORCID ProfileHuda Y. Zoghbi
doi: https://doi.org/10.1101/2022.10.05.510925
Sameer S. Bajikar
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
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Ashley G. Anderson
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
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Jian Zhou
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
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Mark A. Durham
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
3Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
4Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, 77030, USA
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Alexander J. Trostle
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
5Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
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Ying-Wooi Wan
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
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Zhandong Liu
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
5Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
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  • ORCID record for Zhandong Liu
Huda Y. Zoghbi
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
2Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, 77030, USA
3Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
5Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
6Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA
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  • ORCID record for Huda Y. Zoghbi
  • For correspondence: hzoghbi@bcm.edu
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ABSTRACT

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 06, 2022.
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MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
Sameer S. Bajikar, Ashley G. Anderson, Jian Zhou, Mark A. Durham, Alexander J. Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y. Zoghbi
bioRxiv 2022.10.05.510925; doi: https://doi.org/10.1101/2022.10.05.510925
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MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
Sameer S. Bajikar, Ashley G. Anderson, Jian Zhou, Mark A. Durham, Alexander J. Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y. Zoghbi
bioRxiv 2022.10.05.510925; doi: https://doi.org/10.1101/2022.10.05.510925

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