Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Embryonic Development of Neural Map Topography


Science 31 July 2009: Vol. 325. no. 5940, pp. 585 - 590

Pre-Target Axon Sorting Establishes the Neural Map Topography

Takeshi Imai, Takahiro Yamazaki, Reiko Kobayakawa, Ko Kobayakawa, Takaya Abe, Misao Suzuki, Hitoshi Sakano

1 Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0032, Japan.
2 Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan.
3 Division of Transgenic Technology, Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0081, Japan.


Sensory information detected by the peripheral nervous system is represented as a topographic map in the brain. It has long been thought that the topography of the map is determined by graded positional cues that are expressed by the target. Here, we analyzed the pre-target axon sorting for olfactory map formation in mice. In olfactory sensory neurons, an axon guidance receptor, Neuropilin-1, and its repulsive ligand, Semaphorin-3A, are expressed in a complementary manner. We found that expression levels of Neuropilin-1 determined both pre-target sorting and projection sites of axons. Olfactory sensory neuron–specific knockout of Semaphorin-3A perturbed axon sorting and altered the olfactory map topography. Thus, pre-target axon sorting plays an important role in establishing the topographic order based on the relative levels of guidance molecules expressed by axons.

In the vertebrate nervous system, sensory information is spatially encoded in the brain, forming topographic maps that are fundamental for cognition and higher-order processing of sensory information . Molecular mechanisms of topographic map formation have been extensively studied in the visual system. The visual image on the retina is roughly preserved in the tectum, which receives retinal ganglion cell axons. Nearly 50 years ago, Sperry proposed the "chemoaffinity hypothesis," in which target cells present chemical cues to guide axons to their destinations. Axonal projection of retinal ganglion cells is instructed by several pairs of axon guidance molecules that demonstrate graded expression in the retina and tectum.

Olfactory information is also encoded in a topographic map formed on the olfactory bulb (OB), a part of the forebrain. In rodents, odors are detected with ~1000 types of odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) in the olfactory epithelium. Each OSN expresses only one functional OR gene. Furthermore, OSNs expressing a given type of OR converge their axons to a specific glomerulus on each glomerular map in the OB. During olfactory development, OSN axons are guided to approximate locations in the OB by the combination of dorsal-ventral patterning, based on anatomical locations of OSNs in the olfactory epithelium, and anterior-posterior patterning, regulated by OR-derived cyclic adenosine monophosphate (cAMP) signals. The glomerular arrangement along the dorsal-ventral axis appears to be determined by axon guidance molecules expressed in a graded manner along the dorsomedial-ventrolateral axis in the olfactory epithelium, such as Robo-2 and Neuropilin-2. Unlike dorsal-ventral positioning, anterior-posterior positioning of glomeruli is independent of positional information in the olfactory epithelium. Instead, OR-specific cAMP signals determine the expression levels of Neuropilin-1 (Nrp1) in OSN axon termini, forming a gradient of Nrp1. Thus, the olfactory system also uses gradients of axon guidance molecules to form the topographic map.

Pre-target axon sorting affects the topographic map formation in the OB. Olfactory map topography emerges within the axon bundle prior to the axon-target interactions in the OB. Nrp1 regulates pre-target axon sorting. Sema3A expressed by OSNs is required for axon sorting. Nrp1 is the receptor for the secreted repulsive ligand Semaphorin-3A (Sema3A). Sema3A is expressed not only in the target, but also in OSNs. Nrp1 and its repulsive ligand Sema3A are both expressed in OSNs and are involved in axon sorting before targeting on the OB.

Once OSN axons are sorted in the bundle, they need to be oriented along the correct axis before projecting onto a topographic map on the OB. This probably requires positional cues that are derived from the target or that are found along the pathway between the olfactory epithelium and the OB. Sema3A expressed by cells outside of the bundle likely functions as an additional guidance cue to orient the sorted axons along the correct axis for projection onto OB. Sema3A is found in ensheathing glial cells along the medial side of the axon bundles. Involvement of such intermediate cues has been reported for the thalamocortical projection. Surgical and genetic studies indicated that projection sites for retinal ganglion cells are determined by relative, but not absolute, levels of guidance receptors, known as "axonal competition". We propose that the axon-axon interaction is a general strategy to establish the topographic order based on the relative levels of guidance molecules expressed by axons.

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