CRMP4 is required for the positioning and maturation of newly generated neurons in adult mouse hippocampus.

Adult neurogenesis is a phenomenon in which neural stem cells differentiate and mature to generate new neurons in the adult brain. In mammals, the sites where adult neurogenesis occurs are limited to the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone. In the hippocampus, newly generated neurons migrate into the granule cell layer (GCL) and are integrated into neural circuits. Previous studies have revealed that CRMP4, a member of the CRMP family, is expressed in immature neurons in the hippocampal SGZ of the adult brain. However, the role of CRMP4 in adult neurogenesis is unknown. To study the role of CRMP4 in hippocampal adult neurogenesis, we compared adult neurogenesis between wild type and CRMP4-/- mice. In CRMP4-/- mice, the number of doublecortin (DCX)-positive cells was comparable to that in wild-type mice, and some DCX-positive cells were ectopically located in the granule cell layer, suggesting that CRMP4 is involved in the migration of adult neurogenesis. In addition, the number of calretinin-positive new neurons in the SGZ was significantly increased, whereas the number of EdU/NeuN-double positive neurons was decreased in CRMP4-/- mice, suggesting that CRMP4 plays an important role in neuronal maturation. Because CRMP4 is expressed in immature neurons, its expression may regulate the migration from the SGZ to the GCL during neuronal maturation in hippocampal adult neurogenesis.

Regulation of axon pruning of mossy fiber projection in hippocampus by CRMP2 and CRMP4.

Axon pruning facilitates the removal of ectopic and misguided axons and plays an important role in neural circuit formation during brain development. Sema3F and its receptor neuropilin-2 (Nrp2) have been shown to be involved in the stereotyped pruning of the infrapyramidal bundle (IPB) of mossy fibers of the dentate gyrus (DG) in the developing hippocampus. Collapsin response mediator proteins (CRMPs) were originally identified as an intracellular mediator of semaphorin signaling, and the defective pruning of IPB was recently reported in CRMP2-/- and CRMP3-/- mice. CRMP1 and CRMP4 have high homology to CRMP2 and CRMP3, and their expression in the developing mouse brain overlaps; however, their role in IPB pruning has not yet been examined. In this study, we report that CRMP4, but not CRMP1, is involved in IPB pruning during neural circuit formation in the hippocampus. Our genetic interaction analyses indicated that CRMP2 and CRMP4 have distinct functions and that CRMP2 mediates IPB pruning via Nrp2. We also observed the altered synaptic terminals of mossy fibers in CRMP2 and CRMP4 mutant mice. These results suggest that CRMP family members have a distinct function in the axon pruning and targeting of mossy fibers of the hippocampal DG in the developing mouse brain.