Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice

Rakesh Kumar, Clayton R. Hunt, Arun Gupta, Suraj Nannepaga, Raj K. Pandita, Jerry W. Shay, Robert Bachoo, Thomas Ludwig, Dennis K. Burns, Tej K. Pandita

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The brains of ataxia telangiectasia (AT) patients display an aberrant loss of Purkinje cells (PCs) that is postulated to contribute to the observed deficits in motor coordination as well as in learning and cognitive function. AT patients have mutations in the ataxia telangiectasia mutated (ATM) gene [Savitsky et al. (1995) Science 268:1749-1753]. However, in Atm-deficient mice, the neurological defects are limited, and the PCs are not deformed or lost as observed in AT patients [Barlow et al. (1996) Cell 86:159-171]. Here we report that PC-specific deletion of the mouse males absent on the first (mMof) gene (Cre-), which encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac) and influences ATM function, is critical for PC longevity. Mice deficient for PC-specific Mof display impaired motor coordination, ataxia, a backward-walking phenotype, and a reduced life span. Treatment of MofF/F/Pcp2-Cre+ mice with histone deacetylase inhibitors modestly prolongs PC survival and delays death. Therefore, Mof expression and H4K16 acetylation are essential for PC survival and function, and their absence leads to PC loss and cerebellar dysfunction similar to that observed in AT patients.

Original languageEnglish (US)
Pages (from-to)3636-3641
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number9
DOIs
StatePublished - Mar 1 2011

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Keywords

  • Ataxia telangiectasia phenotype
  • Chromatin modification
  • DNA damage response

ASJC Scopus subject areas

  • General

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