Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Abstract

Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1 1/2 ) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1 1/2 mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and faterestricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.

SIRT1 Involved in the Regulation of Alternative Splicing Affects the DNA Damage Response in Neural Stem Cells

“…Unsurprisingly, 455 differentially spliced exons and nearly 50 affected biological processes were identified between CON and IR-treated NSCs. Some were neural cell-related processes such as nervous system development, neuron projection development, dendrite morphogenesis, and negative regulation of astrocyte differentiation, which indicated that DNA damage could affect NSC development, consistent with the findings of a previous study [4]. Furthermore, the expected DDR-related procedures were also included, such as apoptotic signaling, regulation of cyclin-dependent protein kinase activity, and drug response pathways.…”

Immunocytochemical localization of DNA double-strand breaks in human and rat brains

“…Thus, it appears that tonic activation of DNA double-strand breaks in early-born neural progenitors is linked to a progressive differentiation state of neurogenesis. In this context, neural progenitors are extremely sensitive to DNA damage, particularly at different G1 and S phases of development (McKinnon, 2013;Tanori et al, 2013). This may be attributed to the high replication rate of neural progenitors during routine neurogenesis cycles.…”

Role of BRCA1 in brain development

“…This susceptibility is most likely due to the high proliferative rate characteristic of NSCs. IR interferes with the embryonic development of many brain structures, such as the neocortex (3), cerebellum (4), and hippocampus (5). It has been shown that IR induces DNA doublestrand breaks, leading to microcephaly and mental retardation via activation of p53-dependent apoptosis (3).…”