p53 and its novel targets in healthy neurodevelopment and microcephaly, studied in mice.

The tumor suppressor P53 (also named TP53) in humans ((T)p53 in mice) is of pivotal importance for the maintenance of genome stability. About 50% of cancers involve P53 gene mutation, making P53 one of the most extensively investigated genes/proteins. p53 is a transcription factor that can (de)activate genes (“p53 targets”) by binding to specific regulatory DNA sequences. p53 activates genes involved in cell cycle arrest, DNA repair and apoptosis in response to cellular stresses, which cause DNA damage, such as exposure to ionizing radiation. However, recent studies have identified other functions of p53 targets including cellular metabolism, autophagy, cell motility and differentiation. Until now, the role of p53 and its target genes during normal brain development have not been characterized in much detail. We recently identified a number of novel radiation-induced p53 targets that may be important for normal brain function and development. Furthermore, we have found indications that stress-related transcriptional activation of these genes may be the cause of microcephaly. The latter is a neurodevelopmental disorder characterized by a reduction in the size of the brain and can be caused by a reduction of the number of neurons and/or neural progenitors as a result of extensive cell death. We aim to document the role of p53, some of its targets, and its partner and new DNA repair protein Tdp2, in mouse embryonic brain and in the etiology of radiation-induced microcephaly.