Viewpoint Cite This: Biochemistry 2017, 56, 6075-6076
pubs.acs.org/biochemistry
Molecules That Can Rewire the Taste System Zhe He and John R. Carlson* Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States
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identified by virtue of a role in neuronal wiring.3 Semaphorins act as attractants or repellents, of neurons or non-neuronal cells. Some semaphorins, such as SEMA3A, are secreted; others, such as SEMA7A, are membrane-bound. All contain at their N-termini a Sema domain of 500 amino acids, which is a variant of the seven-blade β-propeller fold. Structural differences among the Sema domains of different semaphorins may account for their ability to bind to diverse receptors.4 To determine whether SEMA3A plays a role in the wiring of bitter TRCs to bitter ganglion neurons, the authors generated mice with a conditional deletion of Sema3a in bitter TRCs. In these mice, the wiring appeared to be defective, as judged by functional studies of bitter ganglion neurons. Nearly half of the neurons that responded to bitter compounds also responded to tastants of other qualities, a much greater fraction than in the control. The authors suggested the interpretation that SEMA3A is normally secreted from bitter TRCs and acts positively to promote the formation of connections with bitter neurons. To test this interpretation, the authors ectopically expressed a human Sema3A gene in sweet TRCs. They found an increase in the population of ganglion cells that responded to both sweet and bitter, as if the expression of SEMA3A promoted connections between sweet TRCs and bitter neurons. The number of remaining bitter-specific neurons was reduced further by performing this manipulation in a mutant that lacked SEMA3A in bitter cells. These mice were found to have a defective behavioral response to a bitter compound, quinine. The authors also tested the hypothesis that SEMA7A, which was highly enriched in sweet TRCs, acts in sweet TRCs to promote connections with sweet neurons. They tested this hypothesis by ectopically expressing a human Sema7A gene in bitter TRCs. This misexpression produced a major increase in the number of neurons that respond to both sweet and bitter compounds. Likewise, expression of human SEMA7A in soursensing cells led to an increase in the number of neurons responding to both sweet and sour. In summary, this study highlights semaphorins as molecules that are capable of rewiring the taste system, a system in which cells with different identities are closely packed and must be regenerated frequently. The results provoke a wide variety of intriguing and profound questions. First, through what receptors do SEMA3A and SEMA7A signal in bitter and sweet neurons, respectively? In other systems, SEMA3A signals via neuropilin-1 and a plexin; SEMA7A interacts with a plexin and a neuronal integrin. Lee et al.2 show that neuropilin-1 and several plexins are expressed in a population of ganglion neurons. It would be interesting to
ammals perceive tastes of different qualities: bitter, sweet, sour, salty, and umami. These tastes are sensed via taste buds on the tongue (Figure 1). Each taste bud contains
Figure 1. Taste bud containing taste receptor cells (TRCs). A TRC sensitive to bitter compounds and a TRC sensitive to sweet compounds are indicated. TRCs must form connections with specific ganglion neurons to faithfully transmit taste information to the brain. Lee et al.2 found that two semaphorins, SEMA3A and SEMA7A, are highly enriched in bitter and sweet TRCs, respectively, and can influence the wiring of the system.
on the order of 50−100 taste receptor cells (TRCs), many of which respond to tastants of a specific quality.1 The TRCs connect to ganglion neurons, through which taste information is sent to the brain. TRCs have a short life span and are continuously regenerated via taste stem cells. The newly generated TRCs must connect with appropriate classes of ganglion neurons for the taste system to transmit information faithfully. For example, a newly differentiated bitter-sensing TRC must connect with a bitter-sensing neuron; if it were wired to a sweet-sensing neuron, then the animal might consume a bitter-tasting toxin. The need to form appropriate connections raises a fascinating problem: how do the diverse and continuously regenerating TRCs within a taste bud form appropriate connections? To investigate the molecular basis of this problem, a recent study by Lee et al.2 isolated sweet and bitter TRCs by fluorescence-based cell sorting. RNA from the isolated cells was sequenced, and differentially expressed genes were identified. The roster of genes included a number that had previously been implicated in neuronal wiring. Two of the genes thereby identified were Semaphorin 3A (Sema3A) and Semaphorin 7A (Sema7A), whose expression was highly enriched in bitter and sweet TRCs, respectively. Semaphorins make up a large class of proteins, initially © 2017 American Chemical Society
Received: October 19, 2017 Published: November 8, 2017 6075
DOI: 10.1021/acs.biochem.7b01061 Biochemistry 2017, 56, 6075−6076
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Biochemistry examine the effects of mutating these receptors in bitter and sweet neurons. Second, it would be interesting to visualize directly the interactions between TRCs and neurons at the cellular level, in both the wild type and mutants of Sema3a and Sema7a. Analysis of the localization of SEMA3A, SEMA7A, and their receptors in TRCs and neurons and visualization of the TRC− neuron contacts by GFP reconstitution across synaptic partners (GRASP) or other techniques would help define the cellular basis of these fascinating interactions. Finally, it will be interesting to determine the extent to which the appealing molecular logic presented by Lee et al. is used in other sensory systems.5 Some of these systems, like the taste system, face an especially formidable challenge, maintaining the proper connectivity of closely adjacent sensory cells with their downstream neuronal partners during the course of continual sensory cell replenishment. The use of different semaphorins to keep the system properly wired in such systems seems like an elegant solution to this difficult problem.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhe He: 0000-0001-8875-9852 Funding
This work was supported by National Institutes of Health Grants R01 DC 02174, R01 DC 04729, and R01 DC 11697 to J.R.C. Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Roper, S. D., and Chaudhari, N. (2017) Taste buds: cells, signals and synapses. Nat. Rev. Neurosci. 18 (8), 485−497. (2) Lee, H., Macpherson, L. J., Parada, C. A., Zuker, C. S., and Ryba, N. J. (2017) Rewiring the taste system. Nature 548 (7667), 330−333. (3) Tran, T. S., Kolodkin, A. L., and Bharadwaj, R. (2007) Semaphorin regulation of cellular morphology. Annu. Rev. Cell Dev. Biol. 23, 263−292. (4) Janssen, B. J., Robinson, R. A., Pérez-Brangulí, F., Bell, C. H., Mitchell, K. J., Siebold, C., and Jones, E. Y. (2010) Structural basis of semaphorin−plexin signalling. Nature 467 (7319), 1118−1122. (5) Hong, W., and Luo, L. (2014) Genetic control of wiring specificity in the fly olfactory system. Genetics 196 (1), 17−29.
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DOI: 10.1021/acs.biochem.7b01061 Biochemistry 2017, 56, 6075−6076
