Genetic analysis of BDNF expression cliques and adult neurogenesis in the hippocampus

The subgranular zone of the dentate gyrus of sexually mature mice contains a highly variable number of pluripotent stem cells that produce a stream of intermediate progenitors which give rise to neurons and glial cells. Genetic factors, age, and the environment control variation in the fate and rate of neurogenesis. Discovery of stem cells in the adult CNS has catalyzed wide-ranging research into the molecular control of regeneration and repair. In recent work we have explored the genetic basis of variation in adult neurogenesis in C57BL/6J (B), DBA/2J (D) and the BXD family of inbred mice [1]. Here we exploit expression quantitative trait locus (eQTL) mapping and advanced graph theoretical algorithms to extract and analyze small sets of genes-so-called cliques and paracliques-that have tightly coupled expression with brain-derived neurotrophic factor (BDNF). Isoforms of BDNF are key modulators of neuronal proliferation, dendritic plasticity, and also influence disease susceptibility. Two independent BDNF cliques that are associated with all Bdnf transcripts or dendritic transcripts were studied using gene ontology analysis, direct literature analysis, and eQTL mapping methods. We show that these two Bdnf cliques are modulated by gene variants located on distal Chr 1 (the Fmn2/Qrr1 region) and proximal Chr 19 near Prune2. Prune2, which controls the clique primarily associated with total Bdnf expression, is a novel adult neurogenesis candidate gene with proapoptotic function that has recently been linked to Alzheimer's disease.