Morphogenesis of the dentate gyrus: what we are learning from mouse mutants

The dentate gyrus is one of two locations with continuing neurogenesis in adult mammals. While the function of adult neurogenesis is unknown, it is believed that it is involved in learning and memory. For adult neurogenesis to occur, the dentate gyrus must maintain the appropriate precursor cell niche in the subgranular zone, which is likely to be dependent on the developmental mechanisms at play in forming the dentate gyrus. In this review, we graft a molecular framework onto the known neuroanatomic developmental plan by considering the phenotypes of several mouse mutants that have well characterized dentate gyrus developmental abnormalities. This effort reveals that there are at least six distinct developmental steps that need to occur in the formation of the dentate gyrus, which can be associated with specific gene defects: (1) defining the dentate neuroepithelium; (2) forming the primary radial glial scaffolding; (3) radial migration of granule neurons to form the primordial granule cell layer; (4) establishing the precursor pool in the hilus; (5) radial transformation of the tertiary matrix, and (6) differentiation of dentate granule cells. From this analysis, it is clear that some molecular pathways control multiple steps in the development of the dentate gyrus. For example the Wnt pathway (steps 1, 2, 4) and the chemokine receptor CXCR4 (steps 3, 4) are involved in multiple developmental steps, while the neuronal differentiation gene NeuroD (step 6) and the integrin signaling pathway (step 5) are involved only in discrete stages of the dentate gyrus morphogenesis.