title: Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice.
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 Mof(F/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.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.forename: Arun
authors.initials: A
authors.lastname: Gupta
authors.forename: Suraj
authors.initials: S
authors.lastname: Nannepaga
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Robert
authors.initials: R
authors.lastname: Bachoo
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D017353:Gene Deletion; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D016138:Walking
chemical_list: D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; C045073:Cre recombinase; D019426:Integrases