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Int. J. Mol. Sci. 2014, 15(1), 1554-1573; doi:10.3390/ijms15011554

Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence

Department of Veterinary Sciences, Università di Torino, Via Leonardo da Vinci 44, Grugliasco I-10095, Italy
Istituto Italiano di Neuroscienze (INN), Via Leonardo da Vinci 44, Grugliasco I-10095, Italy
Present address: Miltenyi Biotec GmbH, Bergisch Gladbach 51427, Germany
Present address: Istituto Italiano di Tecnologia (IIT), Genoa 16121, Italy
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 12 November 2013 / Revised: 30 December 2013 / Accepted: 10 January 2014 / Published: 21 January 2014
(This article belongs to the Special Issue Neuroprotective Strategies 2014)
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Phosphorylation of the histone H2AX (γH2AX form) is an early response to DNA damage and a marker of aging and disease in several cells and tissues outside the nervous system. Little is known about in vivo phosphorylation of H2AX in neurons, although it was suggested that γH2AX is an early marker of neuronal endangerment thus opening the possibility to target it as a neuroprotective strategy. After experimental labeling of DNA-synthesizing cells with 5-bromo-2-deoxyuridine (BrdU), we studied the brain occurrence of γH2AX in developing, postnatal, adult and senescent (2 years) mice by light and electron microscopic immunocytochemistry and Western blotting. Focal and/or diffuse γH2AX immunostaining appears in interkinetic nuclei, mitotic chromosomes, and apoptotic nuclei. Immunoreactivity is mainly associated with neurogenetic areas, i.e., the subventricular zone (SVZ) of telencephalon, the cerebellar cortex, and, albeit to a much lesser extent, the subgranular zone of the hippocampal dentate gyrus. In addition, γH2AX is highly expressed in the adult and senescent cerebral cortex, particularly the piriform cortex. Double labeling experiments demonstrate that γH2AX in neurogenetic brain areas is temporally and functionally related to proliferation and apoptosis of neuronal precursors, i.e., the type C transit amplifying cells (SVZ) and the granule cell precursors (cerebellum). Conversely, γH2AX-immunoreactive cortical neurons incorporating the S phase-label BrdU do not express the proliferation marker phosphorylated histone H3, indicating that these postmitotic cells undergo a significant DNA damage response. Our study paves the way for a better comprehension of the role of H2AX phosphorylation in the normal brain, and offers additional data to design novel strategies for the protection of neuronal precursors and mature neurons in central nervous system (CNS) degenerative diseases. View Full-Text
Keywords: H2AX; histone; DNA damage; immunocytochemistry; cell proliferation; apoptosis; neuroprotection; Alzheimer’s disease; Huntington’s disease H2AX; histone; DNA damage; immunocytochemistry; cell proliferation; apoptosis; neuroprotection; Alzheimer’s disease; Huntington’s disease

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Barral, S.; Beltramo, R.; Salio, C.; Aimar, P.; Lossi, L.; Merighi, A. Phosphorylation of Histone H2AX in the Mouse Brain from Development to Senescence. Int. J. Mol. Sci. 2014, 15, 1554-1573.

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