Induction of neurogenesis by IFRD1/PC4 in adult hippocampus

Neurogenesis in the dentate gyrus of the adult hippocampus has been implicated in neural plasticity and memory, as well as in depression. With the aim to understand the molecular mechanisms controlling the proliferation and differentiation of newborn neurons and their integration into the synaptic circuitry we have previously analyzed the processes controlling the differentiation of new adult hippocampal neurons and the effects of its alteration on memory (1,2). We have now investigated the effects on neurogenesis of the gene IFRD1 (interferon- related developmental regulator 1), which has been shown to be involved in the process of neural differentiation and to induce muscle regeneration. To this aim, we have generated a conditionally inducible transgenic mouse expressing IFRD1 under control of a nestin promoter, in staminal and progenitor cells of the dentate gyrus of the hyppocampus and of the subventricular zone, the two neurogenic niches that continue to generate new neurons throughout adulthood. By activating the IFRD1 transgene from conception until two months of age, we observe an increase in the number of new 1- to 5-day-old neurons generated in the dentate gyrus. The molecular mechanism underlying such increase of neurogenesis might involve the ability of IFRD1 to coactivate MEF2C by displacing from it histone deacetylase-4 (HDAC4). MEF2C has in fact been implicated in the development of hippocampal neurons. We are now investigating whether to such increase of neurogenesis corresponds an increase of the integration of new neurons into the synaptic circuitry, and we are testing possible effects of an IFRD1-dependent enhancement of neurogenesis during neurodegenerative processes.