On the scent of how a sense of smell develops

Neurobiologists from Japan and the US have identified a signaling system functioning during vertebrate development that controls the proper positioning of cells giving rise to future olfactory neurons, and their eventual correct wiring to the brain.

Researchers identify factors needed for proper olfactory development

Neurobiologists from Japan and the US have identified a signaling system functioning during vertebrate development that controls the proper positioning of cells giving rise to future olfactory neurons, and their eventual correct wiring to the brain.

During development many cells originate in one place but then migrate to another before they mature into their final functional cell type. One example of this process is the development of the placodes—areas of thickening along the embryonic epithelia that gives rise to organs for hearing, seeing and smelling. This last one—the nasal placode—contains the future nasal epithelia and olfactory neurons. To better understand how these placodes form, scientists have focused their attention recently on a family of small, secreted proteins, the so-called chemokines, which were originally identified as controlling immune cell migration.

Using zebrafish, the team led by Nobuhiko Miyasaka from the RIKEN Brain Science Institute in Wako, has now identified the chemokine Cxcl12a and its receptor, Cxcr4b, as key molecules necessary for the correct positioning of the nasal placode (1).

The team showed that in mutant fish lacking either Cxcl12a or Cxcr4b function some cells failed to join this placode. They further showed that in both types of mutant fish the olfactory neurons developed in the placode, though in most instances they subsequently failed to project axons to the olfactory bulb, a region in the brain some distance from the placode that transmit a sense of smell to higher olfactory centers (Fig. 1 - Click on link below).

The researchers confirmed these findings by showing that experimentally-induced mis-expression of Cxcl12a also perturbed the placode assembly, but unlike loss of its expression (or that of Cxcr4b), it did not affect olfactory axon outgrowth towards the olfactory bulb. Importantly, this suggests that Cxcl12a is not acting as a guidance factor for olfactory axons because ubiquitous mis-expression would have ‘confused’ the axons if it was acting in this way. Rather, Cxcl12a is acting as a ‘permissive factor’ that allows these axons to navigate the local environment.

Previous studies have shown that Cxcl12/Cxcr4 signaling regulates retinal axon projections in zebrafish (2) and motor axon projections in mice (3). Miyasaka therefore says that “Cxcl12/Cxcr4 signaling might be a general, evolutionary conserved molecular tool that allows for and shapes the initial trajectory needed by various growing axons to properly innervate their respective targets.” Insight from future studies could illuminate the molecular mechanisms downstream of these chemokines, which one day may be manipulated to regrow axons on demand.

1. Miyasaka, N., Knaut, H. & Yoshihara, Y. Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development 134, 2459–2468 (2007).

2. Li, Q., Shirabe, K., Thisse, C., Thisse, B., Okamoto, H., Masai, I. & Kuwada J.Y. Chemokine signaling guides axons within the retina in zebrafish. Journal of Neuroscience 25, 1711–1717 (2005).

3. Lieberam, I., Agalliu, D., Nagasawa, T., Ericson, J. & Jessell, T.M. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 47, 667–679 (2005).

Published: 01 Sep 2007

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http://www.rikenresearch.riken.jp/research/291/image_1128.html Figure 1: Live imaging of axon projections from the nasal epithelium into the olfactory bulb in normal (left) and mutant zebrafish lacking functional Cxcr4b (right). The mutant Cxcr4b fish have a variable phenotype, such that some nasal epithelia fail to project axons (yellow arrowheads) and others do not.

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Development

Medicine