Development: The hidden depths of zebrafish skin
The largest organ in the vertebrate body, the skin, performs a wide range of roles such as protecting against infection, sensing the environment, and supporting essential appendages such as hair, feathers and scales. It is also beautifully complex.
In its postembryonic form, vertebrate skin is formed of three layers – the epidermis (the outermost layer), the dermis and the hypodermis – that contain a range of different cell types, each dedicated to a specific function. In zebrafish, for example, some cells create the proteins required for scales to harden and become calcified, while others produce the pigments that give the species its delicate stripe pattern. Despite extensive studies over the past few decades, researchers still do not fully understand how this complexity arises during development. Now, in eLife, David Parichy and colleagues – including Andrew Aman and Lauren Saunders as joint first authors – report that they have classified all the major cell types in zebrafish skin, identified a cell type which was previously unknown, and dissected some of the signalling networks that are essential for development (Aman et al., 2023).
The researchers – who are based at the University of Virginia, the University of Washington and the National Human Genome Research Institute – started by using single-cell transcriptomic analysis to study 35,114 post-embryonic zebrafish skin cells. This approach allowed Aman et al. to establish the ‘RNA profile’ of each individual cell, showing which genes it expresses, and at what level, at a given time.
One of the most interesting findings to emerge from this work was the identification of a group of epidermal cells which expressed genes coding for proteins that are necessary for the formation of enamel (Figure 1). As human cells known as ameloblasts secrete some of the same proteins to create the enamel of our teeth, this result suggests that zebrafish scales could be an alternative model in which to study ameloblast biology in vivo. Meanwhile, it also highlights an ancient connection between fish scales and human teeth, one that may date back 450 million years to the time when the first fish species with calcified outer layers emerged during the Ordovician Period (Sire et al., 2009). In fact, some evidence suggests that teeth may have evolved from certain types of primitive scales (Gillis et al., 2017).

A new cell type in the epidermis of zebrafish, and a new role for the hypodermis in pigmentation.
Zebrafish skin is composed of three layers, each of which contains distinct cell types. For example, the dermis (the middle layer) contains fibroblast cells, pre-scale forming cells and scale forming cells; the latter two cell types support the growth of scale plates which, when coated with a matrix that allows calcification, will become scales. Aman et al. demonstrate the presence of a previously unknown cell type (blue) in the epidermis (the top layer) which expressed genes necessary for enamel formation. Aman et al. also confirm that the hypodermis (the bottom layer) is important for pigment production, being enriched with different types of pigment cells such as xanthophores, melanophores and iridophores.
Image credit: Yue Rong Tan (CC BY 4.0).
To better understand the molecular mechanisms underpinning skin development, Aman et al. applied their approach to cells from various zebrafish mutants (Harris et al., 2008; Lang et al., 2009; McMenamin et al., 2014). In animals with scale defects, the analyses revealed several signalling pathways that act in turn to regulate scale-forming cells at the base of the epidermis. Further in vivo experiments helped to pinpoint key molecular actors in this process, highlighting a specific signalling ligand called Fgf20a, which is also involved in the development and regeneration of scales. Piecing together the RNA profiles of zebrafish mutants with defective pigment development, on the other hand, provided convincing evidence that the hypodermis is not in fact a mere structural layer. Instead, it is essential for pigment cell development and adult stripe pattern formation.
Finally, Aman et al. examined the role of the thyroid hormone on skin development, as this chemical messenger has been implicated in a range of human skin conditions. To do so, they examined the RNA profiles of skin cells from zebrafish in which the thyroid gland had been removed (McMenamin et al., 2014). This analysis revealed several genes whose expression is potentially regulated by this hormone, including a gene called pdgfaa. Further in vivo work showed that over-expressing this gene in fish with low levels of thyroid hormone partially re-established a normal stratification of the dermis, but did not alter how scales were created. Together, these findings should open new opportunities for understanding and treating human skin diseases.
This work illustrates how single-cell transcriptomic profiling can detect rare cell types, infer cell fate trajectories, and identify relevant signalling networks. On its own, however, this method may fall short of capturing the exquisite details of skin development, such as how differentiated skin cells influence the behavior of neighbouring basal stem cells, the way that appendages instruct the growth of nerve projections and blood vessels, or the fact that tension can trigger skin cells to divide without replicating their DNA (Mesa et al., 2018; Ning et al., 2021; Rasmussen et al., 2018; Chan et al., 2022). Only studies in live animals can investigate the role of these cell-to-cell interactions and dynamics in skin development, emphasising a need for multifaceted approaches.
Zebrafish skin may seem less sophisticated than ours at first glance, but Aman et al. have undoubtedly demonstrated that there is much to discover beneath its surface. Developmental biologists can glean valuable insights from looking into it more closely. Given the evolutionary connection between teeth and scales, and now the shared presence of ameloblast-like cells in zebrafish and humans, it may even become possible to unravel why scales, but not human teeth, can regrow throughout life. While it is probably a wild guess, it is fascinating to imagine that one day we may be able to regenerate human teeth thanks to findings made in a toothless little fish.
References
Article and author information
Author details
Publication history
Copyright
© 2023, Tan et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,460
- views
-
- 141
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Developmental Biology
Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.
-
- Developmental Biology
The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.