Are Taste Buds the Key in Understanding Axon Therapies?

            If you read the title, you may be confused. You might be asking yourself “What? Taste buds can tell us about axon regeneration?” Long story short, yes.

I was in the same boat. When I first read the title of these publications I said “really?”. After reading the abstract I was intrigued. Not only do these publications pose a model for axon guidance, they also implicate its importance in the regeneration of axons during neurodegeneration. 

Firstly, a group of researchers in a paper titled Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae gathered data demonstrating the critical role of Ephs/Ephrins in axon development (1). In this paper, the researchers used a murine model of taste bud innervation to demonstrate that without Ephrin signaling being present in the tongue, proper innervation of the taste buds from the geniculate ganglion was not possible (1).

Specifically, this group of researchers focused on EphB1/2 and Ephrin-B to derive a better understanding of the way in which these axons manage to reach their targets (1). 

In vitro, the group of researchers analyzed geniculate neurite outgrowth on coverglasses streaked with ephrin-B1 (1). I won’t bore you with too many details but importantly, they discovered that when each streak consisted of 40 ug/ml ephrin-B1, a strong repulsion of the outgrowth could be observed (1). In simpler terms, since the axons followed the lines streaked with ephrin and did not demonstrate a ton of crossing over, they must have been repulsed by the ephrin-B1 streaked on the coverglass (1). Obviously the group of researchers also gave the results of the multiple control examples done, further supporting their initial observation (1).

But how does the tongue play into this? Well I explained the in vitro approach, but in vivo the researchers used the tongues of mice to demonstrate this same concept (1). Quick biology lesson: The fungiform papillae (taste buds) in mice, are innervated by axons projecting from the geniculate ganglion (1). That’s enough biology for one day. Anyway, in vivo to demonstrate the need for ephrin-B1 to guide these axons into place, they used EphB1/B2 (ephrin-B1’s receptor) knockout mice, and comparatively analyzed the innervation of their taste buds with wild type controls (1). Surprise surprise, they found that the papillae in knockout mice were barely innervated, if at all (1). “Barely” is likely a result of other ephs/ephrins being involved in guidance, just not at the same level (1).

So why does this matter? Well, recent studies have come out suggesting that ephs/ephrins play an important role not only in innervation of axon targets, but also in axon regeneration (2). In the review article Classic axon guidance molecules control correct nerve bridge tissue formation and precise axon regeneration, researchers compiled extensive data analyzing the peripheral nervous system, its regenerative capabilities, and ephs/ephrins role in that regeneration (2). Specifically, they demonstrated that in the nerve bridge of ephB2 knockout mice, axons could not regenerate in the same organized way as in control mice (2). The reason why is believed to be Schwann cells not expressing ephB2 in the knockout mice (2). Without ephB2, Schwann cells were unable to correctly associate with axons in the nerve bridge thus leading to flawed regeneration (2). 

Further, new studies are coming out such as Ephs and ephrins implicating abnormal expression of ephs/ephrins in not only cancer, but neurodegenerative diseases such as Alzheimer's (AD) and Parkinson’s (PD) as well (3). The author’s note that clinical trials looking into therapeutic approaches based around ephs/ephrin in cancer are already underway, but approaches for neurodegenerative diseases are still far off (3). The article mainly explains that in patients with PD and AD, an abnormal expression of specific ephs/ephrins has been documented, leading researchers to believe that something of value may arise when it comes to looking into therapeutic approaches utilizing ephs/ephrins in AD and PD models (3).

Bringing it all together, ephs/ephrins are an amazingly important receptor/ligand pair that are not only responsible for making sure axons are put in the right place but, also responsible for precise regeneration of axons that may degrade such as those in the PNS (1,2,3). 

In my opinion, looking further into how exactly we can manipulate this receptor/ligand pair will become extremely important in fighting disorders such as AD or PD. And rightfully so. If abnormal expression of ephs/ephrins is a key player in the pathology of these disorders, correcting that abnormality is a key player in counteracting these disorders. 

References:

1. Treffy RW, Collins D, Hoshino N, Ton S, Katsevman GA, Oleksiak M, Runge EM, Cho D, Russo M, Spec A, et al. Ephrin-B/EPHB signaling is required for normal innervation of lingual gustatory papillae. Developmental Neuroscience. 2016;38(2):124–138. doi:10.1159/000444748

2. Dun X-P, Parkinson DB. Classic axon guidance molecules control correct nerve bridge tissue formation and precise axon regeneration. Neural Regeneration Research. 2020;15(1):6. doi:10.4103/1673-5374.264441

3. Taylor H, Campbell J, Nobes CD. Ephs and Ephrins. Current Biology. 2017;27(3). doi:10.1016/j.cub.2017.01.003