Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice

Ryan M. Walsh, Erica Y. Shen, Rosemary C. Bagot, Anthony Anselmo, Yan Jiang, Behnam Javidfar, Gregory J. Wojtkiewicz, Jennifer Cloutier, John W. Chen, Ruslan Sadreyev, Eric J. Nestler, Schahram Akbarian () and Konrad Hochedlinger ()
Additional contact information
Ryan M. Walsh: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Erica Y. Shen: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Rosemary C. Bagot: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Anthony Anselmo: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Yan Jiang: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Behnam Javidfar: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Gregory J. Wojtkiewicz: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School
Jennifer Cloutier: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
John W. Chen: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School
Ruslan Sadreyev: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital
Eric J. Nestler: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Schahram Akbarian: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Konrad Hochedlinger: Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of PHF8 have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a Phf8 knockout allele in mice to examine the consequences of Phf8 loss for development and behaviour. Phf8 deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of Phf8. We further observe misregulation of serotonin signalling within the prefrontal cortex of Phf8 deficient mice and identify the serotonin receptors Htr1a and Htr2a as direct targets of PHF8. Our results clarify the functional role of Phf8 in mammalian development and behaviour and establish a direct link between Phf8 expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.

Date: 2017
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DOI: 10.1038/ncomms15142

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