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.

Neurons that synthesize GnRH are critical brain regulators of the reproductive axis, yet they originate outside the brain and must migrate over long distances and varied environments to get to their appropriate positions during development. Many studies, past and present, are providing clues for the types of molecules encountered and movements expected along the migratory route. Recent studies provide real-time views of the behavior of GnRH neurons in the context of in vitro preparations that model those in vivo. Live images provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more alterations in direction after they enter the brain. The heterogeneity of molecular phenotypes for GnRH neurons likely ensures that multiple external factors will be found that regulate the migration of different portions of the GnRH neuronal population at different steps along the route. Molecules distributed in gradients both in the peripheral olfactory system and basal forebrain may be particularly influential in directing the appropriate movement of GnRH neurons along their arduous migration. Molecules that mediate the adhesion of GnRH neurons to changing surfaces may also play critical roles. It is likely that the multiple external factors converge on selective signal transduction pathways to engage the mechanical mechanisms needed to modulate GnRH neuronal movement and ultimately migration.

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