Spatio-temporal gradient of cortical neuron death contributes to microcephaly in knock-in mouse model of ligase 4 syndrome

Cells of the developing central nervous system are particularly susceptible to formation of double-stranded DNA breaks (DSBs) arising from physiological and/or environmental insults. Therefore, efficient repair of DSBs is especially vital for maintaining cellular health and proper functioning in the developing brain. Here, we demonstrate increased expression of DSB initiating and non-homologous end joining repair machinery in newborn neurons in the developing brains of both mouse and human. In parallel, we provide the first characterization of the brain phenotype in the Lig4R278H/R278H (Lig4R/R) mouse model of DNA Ligase 4 (LIG4) syndrome, in which a hypomorphic Lig4 mutation, originally identified in patients, impedes non-homologous end joining.
Source: American Journal of Pathology - Category: Pathology Authors: Source Type: research