Hey fellow homo sapiens

Ever stop and wonder: how much of you… is really you?

Now you’re thinking, “Did this bozo really just ask me if all of me… is me?”

Yeah, I did. Stay with me.

Have you ever wondered who you’d be if you grew up somewhere else? Had different caregiver(s)? Maybe been in a different school? Personally, I think if I was born in the Netherlands, I’d probably be taller… maybe even own a bike that wasn’t trying to kill me every time I ride it.

But seriously, so much of who we are is shaped by our environment. And yes, it’s deeper than spotify playlists, maybe not so much for astrological signs.

In psychology, this whole debate is called nature vs nurture. The idea that who we become is part blueprint (genes), part sculptor (environment). And it turns out, this principle doesn’t just apply to people. It holds up at the cellular level too.

Correcto, I’m talking about cells. The smallest functional units of life. Even they aren’t immune to existential identity crises.

When I think of cell determination, I think of gene expression, promoters, codons… But cells also respond to where they are. If a cell moves to a new “neighborhood”, (different concentration gradients, new cell-to-cell group chats, changes in the extracellular matrix) it might just start a whole new life.

And that brings me to the neural crest in zebrafish. These cells migrate from the boundary between neural and non-neural ectoderm, travel through the embryo, and eventually… settle down, get a job, maybe start a family.

But here’s the fun part: not all neural crest cells are locked by fate but respond to specific local cues. Raible and Eisen expose this idea using early and late migrating neural crest cells.

Normally: early migrators- typically become sensory neurons and late migratory neurons- typically become sympathetic neurons.

But if you get rid of the early migrators (in a totally ethical cell-assassination kind of way), those late migrators who are sympathetic neurons suddenly become sensory neurons. Filling in the role of the missing early migrators.

Basically: no one’s locked into their fate. Even cells can get divorced, move to a new city, and start over as someone completely different.

To explore how location might affect already differentiated neurons Wright et al. 2020 did some cool in vivo experiments in zebrafish.

To recap DRG neurons = early migrating neural crest > stop dorsally > become glutamatergic sensory neurons AND Sympathetic neurons = late migrating > keep moving ventrally to the notochord > become catecholaminergic autonomic neurons.

But some DRG neurons are observed to first stop in their normal DRG location and then (maybe confused by google maps) migrate their somata ventrally to where the normal sympathetic neurons are usually found. An increase in these ectopic positioned of DRG neurons compared to control are further observed with the knock down of nav1.6 sodium channel (with morpholinos).

At first glance these DRG neurons look pretty normal despite their atypical location, as they express HuA (a marker of differentiated neurons) and extended axons dorsally and ventrally, similar to normal positioned DRG neurons.

But the story doesn’t end there, in a follow up experiment they found an increased number of TH+/HuA+ neurons in the territory of sympathetic ganglia for 11 dpf nav1.6 morphant embryos compared with controls. Where are these party buses of extra neurons are coming from? Researchers introduced neurogenin mutants; which lose a transcription factor essential for DRG neurons (so none are born). In this genotype, 1.6mo did not increase the number of TH+/HuA+ neurons within the sympathetic ganglia. Which suggest that DRG neurons provided the increased number of SG neurons present in nav1.6 morphants.

So, now what is sick about this paper, is when we enter into figure 4,6 and 7. They start to go deeper and use photoconvertible Kaede protein in the elavl3:Kaede transgenic line to track individual DRG neurons over time. And the DRG neurons, which started as sensory, eventually ended up in the sympathetic region, now can be seen to express TH (molecular marker specific to sympathetic neurons) WHICH SUGGEST TRANSDIFFERENTIATION!

To confirm that this wasn’t just a fluke, they looked at Figure 4, where they compared: a. control embryo, b. nav1.6 morphant embryo with correct positioning, and c. nav1.6 morphant embryo with ectopic positioning.

In scenario C, you can see that the ectopic DRG neurons have characteristic of sympathetic ganglia, as they have processes extending laterally. This figure highlights the conclusion that environmental context can drives phenotype.

They further investigate if these transdifferentiated neurons keep their jobs or get new jobs, they ran a touch response assay. Normally, DRG neurons mediate touch reflex. They compared nav1.6 siblings (which are wildtype phenotype), 1.6 control morpholino injection, nav1.6 morpholino and nav1.6 mutant. In both, mutants and morphant nav1.6 DRG were present; however their function where impaired. This comparison is crucial because it confirms that the observed neuronal migration and transdifferentiation are due to specific loss of nav1.6 function, not off-target or transient effects.

Lastly if you’re not convinced yet, figure 7  is the golden figure that presents the TH+ cells. In 13-15 dpf larvae, normally positioned DRG neurons rarely express TH. By contrast, the majority of SG neurons do express TH. A significant number of migratory DRG neurons express TH. However, the genotype of the embryo did not affect the percent of TH+ normally positioned DRG, SG or migratory DRG (light-blue bars, nav1.6 siblings; dark-blue bars, nav1.6 mutants; white bars, all embryos pooled regardless of genotype).

This paper didn’t just show that neurons can change addresses, it proved they can redefine themselves when they do. If you didn’t learn anything from this paper, just know that nothing is fate restricted, so go do whatever you want. That said, the paper is not perfect, there is no functional validation that these cells behave like sympathetic neurons and there’s ambiguity if nav1.6 knockdown promotes transdifferentiation directly or maybe facilitates migration.