[P44]: Role of the proneural gene neurogenin2 in development of the dentate gyrus of the hippocampus

Proneural basic helix loop helix (bHLH) transcription factors are important regulators of neurogenesis. Here we focused on the role of the proneural protein Neurogenin2 (Ngn2), in regulation of neurogenesis in the dentate gyrus (DG) of the hippocampus. The DG is known to play an important role in spatial learning and memory but little is known of the molecular mechanisms underlying its development. Neurons in the DG are produced by three pools of progenitor cells, or matrices, generated sequentially during late embryogenesis and early post natal life in the mouse (Altman and Bayer, 1990). The ventricular zone (VZ) of the hippocampus constitutes the primary matrix, a migratory population of progenitors emanating from the VZ form the secondarty matrix, while a group of progenitors that settles in the inner part of the nascent dentate gyrus form the tertiary matrix, which continues to produce new neurons in the dentate gyrus throughout life. We found that Ngn2 is expressed in progenitors in all three matrices in the embryonic, postnatal and adult DG. Using Ngn2-GFP reporter mice, we demonstrate that Ngn2+ cells give rise to most granular neurons of the dentate gyrus. Using Ngn2 null mutant mice, we show that Ngn2 is required for normal development of the dentate gyrus. Lack of Ngn2 results in a defect in generation of progenitors in the three matrices of the DG, in their differentiation and in a partial loss of DG neurons. Interestingly, expression of NeuroD, a bHLH differentiation gene which is a target of Ngn2 in other parts of the nervous system and has been implicated in DG genesis, remains expressed in progenitors that fail to differentiate. Thus, Ngn2 and an unknown parallel pathway synergistically regulate neurogenesis in the developing DG.