The role of ATM responding to DNA damage induced by Xrcc1 deficiency during oligodendrocyte genesis

Abstract

Ataxia telangiectasia (A-T) is a prime example of hereditary disease about DNA damage signaling and repair protein deficiency. A-T is an autosomal recessive neurodegenerative disorder associated the defective ATM (Ataxia telangiectasia mutated) gene that is estimated to affect 1 in 40,000-300,000 people. The clinical features manifested in A-T patients are multisystem symptoms, including cerebellar atrophy, ataxia, abnormal eyes movement, telangiectatic blood vessel, immunodeficiency and hyper-radiosensitivity. Currently there is no cure and no way to slow neuropathological progression of the A-T patients. Because, different from other animal models to mimic diseases with DNA repair protein deficiency, ATM-/- mice do not recapitulate the phenotypes of A-T patients, making it difficult to study the mechanism of neurological phenotypes of this disease in mice.

To make the proper mice model for A-T, we generated Xrcc1 and Atm double knockout mice (hereafter referred to as Xrcc1nes-cre; Atm-/-) to determine the function of DNA damage sensor kinase Atm upon persistent DNA damage condition by Xrcc1 inactivation during brain development. Xrcc1 is a scaffolding protein that is recruited to DNA single strand break site with several interacting proteins such as PARP1, DNA polymeraseβ and Ligase 3. Loss of Xrcc1 led to the persistence of endogenous DNA strand breaks. Xrcc1nes-cre; Atm-/- mouse recapitulates the neurological phenotypes of A-T patients including cerebellar ataxia, cerebellar atrophy, defect of Purkinje cell and dysmyelination in the brain. In the case of dysmyelination, this is a subset of white matter disorders characterized by differentiation defect of oligodendrocytes, also known as leukodystrophy.

We found that neurons and astrocytes in the Xrcc1nes-cre; Atm-/- brain underwent normal differentiation and maturation in vivo and in vitro. But, fully mature oligodendrocyte markers, MBP, PLP and CNPase were downregulated in the Xrcc1nes-cre; Atm-/- mouse cortex and cerebellum. But, the preceding state of fully mature oligodendrocytes, oligodendrocyte progenitor cells (OPC) were intact without any defect such as cell cycle progression and cell death in vivo and in vitro. This outcome was affected by the low protein levels of the oligodendrocyte transcription factor, Olig1. Taken together, our data demonstrate Atm is critical for the proper development of cerebellum and neural cell differentiation, especially oligodendrocytes.