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

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2011; 108(9):3636-41. DOI: 10.1073/pnas.1016524108
Source: PubMed


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.

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Available from: Suraj Nannepaga, Feb 04, 2015
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    • "Mice deficient for Purkinje cell-specific Mof display impaired motor coordination, ataxia, a backward-walking phenotype, and a reduced life span, similar to A-T. Treatment of Mof(F/F)/Pcp2-Cre(+) mice with HDAC inhibitors modestly prolongs Purkinje cell survival and delays death.52 Increased trimethylation of histone H3 on Lysine at position 27 (Lys27) (H3K27me3) mediated by polycomb repressive complex 2 is also important in the A-T phenotype. "
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    ABSTRACT: Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood-brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.
    Full-text · Article · Sep 2014 · The Application of Clinical Genetics
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    • "Afterwards, studies performed on mammalian cells and tumor biopsies indicated that MOF is crucial to several cell functions such as cell proliferation and differentiation , DNA damage repair, autophagy and tumorigenesis [65e 67]. In vivo, a Purkinje cells-specific deletion of MOF in the cerebellum produced neurological abnormalities including impaired motor coordination, ataxia and a backward-walking phenotype [68]. The present work demonstrates that mediobasal hypothalamic MOF is involved in the regulation of energy homeostasis through an activation of polysialylation. "
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    ABSTRACT: Overfeeding causes rapid synaptic remodeling in hypothalamus feeding circuits. Polysialylation of cell surface molecules is a key step in this neuronal rewiring and allows normalization of food intake. Here we examined the role of hypothalamic polysialylation in the long-term maintenance of body weight, and deciphered the molecular sequence underlying its nutritional regulation. We found that upon high fat diet (HFD), reduced hypothalamic polysialylation exacerbated the diet-induced obese phenotype in mice. Upon HFD, the histone acetyltransferase MOF was rapidly recruited on the St8sia4 polysialyltransferase-encoding gene. Mof silencing in the mediobasal hypothalamus of adult mice prevented activation of the St8sia4 gene transcription, reduced polysialylation, altered the acute homeostatic feeding response to HFD and increased the body weight gain. These findings indicate that impaired hypothalamic polysialylation contribute to the development of obesity, and establish a role for MOF in the brain control of energy balance.
    Full-text · Article · Sep 2014 · Molecular Metabolism
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    • "siRNA treatment of cell lines was performed as described (Gupta et al., 2005, 2008; Pandita, 2006). Mutant generation, siRNA transfection, immunofluorescence, and protein retention assay were carried out as previously described (Agarwal et al., 2008; Gupta et al., 2005, 2008, 2009; Hunt et al., 2007; Kumar et al., 2011; Pandita et al., 1999, 2006; Pandita, 2006; Sharma et al., 2003a, 2003b, 2010; Singh et al., 2013). Site-directed mutagenesis of MOF-T392 as well as in vitro kinase assays were performed to confirm that MOF-T392 phosphorylation is ATM dependent. "
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    ABSTRACT: Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.
    Full-text · Article · Jun 2014 · Cell Reports
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