Disruption to schizophrenia-associated gene Fez1 in the hippocampus of HDAC11 knockout mice

Dale T Bryant,Christian Landles,Caroline L Benn,Gillian P Bates,Thomas Rosahl,Joshua K Duckworth,Aikaterini S Papadopoulou,Agnesska C Benjamin

doi:10.1038/s41598-017-11630-1

Dale T Bryant, Christian Landles + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-11630-1

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Abstract

Histone Deacetylase 11 (HDAC11) is highly expressed in the central nervous system where it has been reported to have roles in neural differentiation. In contrast with previous studies showing nuclear and cytoplasmic localisation, we observed synaptic enrichment of HDAC11. Knockout mouse models for HDACs 1–9 have been important for guiding the development of isoform specific HDAC inhibitors as effective therapeutics. Given the close relationship between HDAC11 and neural cells in vitro, we examined neural tissue in a previously uncharacterised Hdac11 knockout mouse (Hdac11KO/KO). Loss of HDAC11 had no obvious impact on brain morphology and neural stem/precursor cells isolated from Hdac11KO/KO mice had comparable proliferation and differentiation characteristics. However, in differentiating neural cells we observed decreased expression of schizophrenia-associated gene Fez1 (fasciculation and elongation protein zeta 1), a gene previously reported to be regulated by HDAC11 activity. FEZ1 has been associated with the dendritic growth of neurons and risk of schizophrenia via its interaction with DISC1 (disrupted in schizophrenia 1). Examination of cortical, cerebellar and hippocampal tissue reveal decreased Fez1 expression specifically in the hippocampus of adult mice. The results of this study demonstrate that loss of HDAC11 has age dependent and brain-region specific consequences.

Highlights

Histone deacetylase 11 (HDAC11) is the most recently identified member of the HDAC family[1], with homologues identified in most species examined[2,3]
This appeared to result from a regulatory role upstream of FEZ1, as they show that Histone Deacetylase 11 (HDAC11) deacetylates BUBR1 (Budding uninhibited by benzimidazole 1-related protein kinase), relieving its inhibition of CDC20/APC, allowing that to ubiquitinate FEZ1 and its degradation
HDAC11 Expression Increases with Neural Differentiation with Nuclear and Synaptic Localisation

Summary

Introduction

Histone deacetylase 11 (HDAC11) is the most recently identified member of the HDAC family[1], with homologues identified in most species examined[2,3]. As previous studies report a role for HDAC11 in cell proliferation and neural differentiation, the aim of this study was to examine the nervous system in a previously uncharacterised Hdac[11] knockout mouse. We further observed specific decrease in Fez[1] gene expression in the hippocampi of adult Hdac11KO/KO mice This suggests that HDAC11 has an age-dependent, brain region specific function in regulating FEZ1, a gene associated with schizophrenia. This is important because it demonstrates that the regulatory role of HDAC11 in the hippocampus is developmentally regulated. Given previous associations between HDAC11, FEZ1 and schizophrenia, a goal of future research should be to examine the performance of homozygous Hdac[11] knockout mice in behavioural tests

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