Semaphorin 3A (Sema3A) is a membrane-associated secreted protein that has chemorepulsive properties for neuropilin-1 (npn-1)-expressing axons. Although mice lacking the Sema3A protein display skeletal abnormalities and heart defects, most axonal projections in the CNS develop normally. We show here that Sema3A is expressed in the lamina propria surrounding the olfactory epithelium (OE) and by ensheathing cells in the nerve layer of the ventral olfactory bulb (OB) throughout development. Subsets of sensory neurons expressing npn-1 are distributed throughout the OE and extend fibers to the developing OB. In wild-type mice, npn-1-positive (npn-1 ϩ ) axons extend to lateral targets in the rostral OB and medial targets in the caudal OB, avoiding regions expressing Sema3A. In Sema3A homozygous mutant mice, many npn-1 ϩ axons are misrouted into and through the ventral nerve layer, beginning as early as embryonic day 13 and continuing at least until birth. At postnatal day 0, npn-1 ϩ glomeruli are atypically located in the ventral OB of Sema3A Ϫ/Ϫ mice, indicating that aberrant axon trajectories are not corrected during development and that connections are made in inappropriate target regions. In addition, subsets of OCAM ϩ axons that normally project to the ventrolateral OB and some lactosaminecontaining glycan ϩ axons that normally target the ventral OB are also misrouted in Sema3A mutants. These observations indicate that Sema3A expression by ensheathing cells plays an important role in guiding olfactory axons into specific compartments of the OB.
Luteinizing hormone-releasing hormone (LHRH) neurons migrate from the vomeronasal organ (VNO) to the forebrain in all mammals studied. In mice, most LHRH neuron migration is dependent on axons that originate in the VNO but bypass the olfactory bulb and project into the basal forebrain. Thus, cues that regulate the trajectories of these vomeronasal axons are candidates for determining the destination of LHRH neurons. Using in situ hybridization techniques, we examined the expression of Deleted in colorectal cancer (DCC), a vertebrate receptor for the guidance molecule netrin-1, during development of the olfactory system. DCC is expressed by cells in the olfactory epithelium (OE) and VNO, and in cells migrating from the OE and VNO from embryonic day 11 (E11) to E14. Some DCC(+) cells on vomeronasal axons in the nose also express LHRH. However, DCC expression is downregulated beginning at E12, so few if any LHRH neurons in the forebrain also express DCC. In rat, DCC is expressed on TAG-1(+) axons that guide migrating LHRH neurons. We therefore examined LHRH neuron migration in DCC(-/-) mice and found that trajectories of the caudal vomeronasal nerve and positions of LHRH neurons are abnormal. Fewer than the normal number of LHRH neurons are found in the basal forebrain, and many LHRH neurons are displaced into the cerebral cortex of DCC(-/-) mice. These results are consistent with the idea that DCC regulates the trajectories of a subset of vomeronasal axons that guide the migration of LHRH neurons. Loss of DCC function results in the migration of many LHRH neurons to inappropriate destinations.
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