Grant: Project Grant

In the developing brain, the birth of neurons is followed by the death of 20-40% of these neurons, raising the question of the importance of such demise for the adult brain. Cajal-Retzius cells (CRs) - pioneer neurons of the embryonic brain but then almost completely disappear - present a unique system to address this question. CRs are organizers of early brain development. They secrete protein factors to regulate the migration of other neurons to build proper architecture of the brain. They also act as "placeholders" that form transient neuron-neuron connections to ensure functional assembly of the brain network. Despite their important roles in brain development, the vast majority of CRs are destined to die during early postnatal life in mice as well as in humans. Incomplete CR cell removal has been described in human brain pathologies including epilepsy, opening the intriguing possibility that CR cell death plays a constructive role in sculpting the mature cerebral cortex. Here, we propose a series of experiments to probe the mechanism that drives CR cell death in the developing brain and investigate how abnormal CR cell survival impinges on adult brain function and contributes to seizure susceptibility. Our work will not only provide novel insight into CR cell biology but will also address the role of CR death and persistence in different brain regions. As abnormal CR cell survival is linked to epilepsy, our study will also shed light on the pathogenic mechanisms of epileptic disorders.