Semaphorin 3A Is Required for Guidance of Olfactory Axons in Mice

Abstract

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.

Cellular Strategies of Axonal Pathfinding

“…The chemotactic cues hypothesized by Cajal would fall into this category. For example, Semaphorin3A acts as a secreted repellent that prevents entry of early arriving olfactory axons into the chick olfactory bulb (Luo et al 1993;Renzi et al 2000), or in the mouse olfactory system, helps to map sensory axons from the epithelium onto specific regions of the olfactory bulb (Schwarting et al 2000;Taniguchi et al 2003;Imai et al 2009). Netrin/ unc6 is a secreted chemotactic signal produced at the ventral midlines of both vertebrates and invertebrates.…”

Anosmin-1a is required for fasciculation and terminal targeting of olfactory sensory neuron axons in the zebrafish olfactory system

“…Semaphorin3A and EphrinA have been identified as key factors for proper axon sorting within the olfactory nerve layer (Schwarting et al, 2000;Tanigusi et al, 2003) and termination of OSN axons onto precisely defined glomeruli (Cutforth et al, 2003), respectively, in rodents. Miyasaka et al (2005) identified Robo2/Slits as the components of a signalling pathway that play a key role in the guidance of nascent OSN axons to presumptive OBs in zebrafish embryos.…”

Cranial expression of class 3 secreted semaphorins and their neuropilin receptors

“…There are five other members of the class 3 family of semaphorins (Semaphorin Nomenclature Committee, 1999). Between them, they regulate the formation of neuronal networks in many regions of the CNS, including the hippocampus, cerebral cortex, and olfactory system (Chedotal et al, 1998;Polleux et al, 1998;Schwarting et al, 2000;Pozas et al, 2001;Cloutier et al, 2002;Walz et al, 2002;Taniguchi et al, 2003). In addition to directing growth cone movements, they regulate the migration of cells, including neural crest and neuronal progenitor cells (Song et al, 1998;Eickholt et al, 1999;Bagnard et al, 2001;Kawasaki et al, 2002) and, thus, may play a role in shaping anatomic structures.…”