Epidermal threads reveal the origin of hagfish slime
Abstract
Fiber-reinforced soft materials possess high flexibility with high strength but are rare in nature. Hagfishes can produce a tough, fibrous slime within a fraction of a second by ejecting two cellular products, mucus and threads, into seawater. With thousands of silk-like threads, the slime is highly effective in defending against large predators. However, the evolutionary origin of hagfish slime remains unresolved, with the presence of another, putatively homologous thread in the epidermis providing circumstantial evidence for an epidermal origin. Here, we investigated the epidermal threads produced in hagfish skin. We found that these threads average ∼2 mm in length and ∼0.5 μm in diameter, or ∼80 times shorter and ∼4 times thinner than the slime threads, characterizing the second longest intracellular fiber. The entire hagfish body is covered by a dense layer of epidermal thread cells, with each square millimeter of skin storing a total of ∼96 cm threads. Experimentally induced damage to a hagfish’s skin caused the release of threads, which together with mucus, formed an adhesive epidermal slime that is more fibrous and less dilute than the defensive slime. Transcriptome analyses further revealed that the epidermal threads are ancestral to the slime threads, with duplication and diversification of thread genes in parallel with the evolution of slime glands. These results support an epidermal origin of hagfish slime and slime glands, as driven by predator selection for stronger and more voluminous slime.
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Author Response
Reviewer #1 (Public Review):
The authors set out to answer the standing mystery of an origin of a unique and complex system that is hagfish slime. They formulated a cogent scenario for the co-option of epidermal thread cells and mucous cells into slime and slime glands. Both histology and EM images back this up. It is a delight to see detailed and careful morphological analysis of both the cells and the secretion. The weakness of the manuscript lies in: a) the absence of an alternative hypothesis (therefore the lacking sense of hypothesis testing); and b) oversimplification and insufficient description of results in transcriptomic and phylogenetic comparison.
These are both key elements of the narrative. Because all the data "support" the only scenario considered in this paper, it could risk giving the impression of …
Author Response
Reviewer #1 (Public Review):
The authors set out to answer the standing mystery of an origin of a unique and complex system that is hagfish slime. They formulated a cogent scenario for the co-option of epidermal thread cells and mucous cells into slime and slime glands. Both histology and EM images back this up. It is a delight to see detailed and careful morphological analysis of both the cells and the secretion. The weakness of the manuscript lies in: a) the absence of an alternative hypothesis (therefore the lacking sense of hypothesis testing); and b) oversimplification and insufficient description of results in transcriptomic and phylogenetic comparison.
These are both key elements of the narrative. Because all the data "support" the only scenario considered in this paper, it could risk giving the impression of a just-so story. My reading of the results of their transcriptomic and phylogenetic analyses is more nuanced than explained in the paper. For example, the authors didn't explain in sufficient detail how the data summary in Fig. 5 "demonstrate" that the epidermal thread cells are "ancestral", and that the diversity of alpha and gamma thread biopolymer genes is a prerequisite to slime (without a functional analysis), or that the gene duplication events facilitated the origin of hagfish slime.
Thank you for these thoughtful comments.
We have made extensive changes to address the two issues raised by the reviewer. For the first one, we added discussion of an alternative hypothesis, namely a cloacal origin of hagfish slime glands (see Line 369). For the second, we added new transcriptomic data from a second species (E. stoutii), and provided more detailed phylogenetic analyses and explanations. Details are provided below and can be seen in the revised manuscript.
Reviewer #2 (Public Review):
The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. I appreciate the careful and detailed measurements and images that the authors provide. The results presented here will surely be extremely important for researchers working on this particular organism and those interested in understanding the evolution, biomedical relevance, and biochemistry of mucus. However, I had difficulty contextualizing the findings in broader biological questions (e.g., the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution). I also think that the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative transcriptomic data may be premature.
Thank you for the thoughtful comments. In this revision, we have rewritten several sections and reorganized the Introduction for clearer readability. Also, we added discussion of an alternative hypothesis that the slime glands might be derived from cloacal glands (see Discussion, Line 369). Further, we provided more detailed transcriptomic data and phylogenetic analyses, along with enriched interpretations, to address the evolution of thread genes.
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eLife assessment
The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. It is a careful and detailed measurement with clear images. However, there is a need for a better contextualizing of the findings as a broader biological question, including the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution. Furthermore, the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative transcriptomic data need to be better supported.
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Reviewer #1 (Public Review):
The authors set out to answer the standing mystery of an origin of a unique and complex system that is hagfish slime. They formulated a cogent scenario for the co-option of epidermal thread cells and mucous cells into slime and slime glands. Both histology and EM images back this up. It is a delight to see detailed and careful morphological analysis of both the cells and the secretion.
The weakness of the manuscript lies in: a) the absence of an alternative hypothesis (therefore the lacking sense of hypothesis testing); and b) oversimplification and insufficient description of results in transcriptomic and phylogenetic comparison. These are both key elements of the narrative. Because all the data "support" the only scenario considered in this paper, it could risk giving the impression of a just-so story. My …
Reviewer #1 (Public Review):
The authors set out to answer the standing mystery of an origin of a unique and complex system that is hagfish slime. They formulated a cogent scenario for the co-option of epidermal thread cells and mucous cells into slime and slime glands. Both histology and EM images back this up. It is a delight to see detailed and careful morphological analysis of both the cells and the secretion.
The weakness of the manuscript lies in: a) the absence of an alternative hypothesis (therefore the lacking sense of hypothesis testing); and b) oversimplification and insufficient description of results in transcriptomic and phylogenetic comparison. These are both key elements of the narrative. Because all the data "support" the only scenario considered in this paper, it could risk giving the impression of a just-so story. My reading of the results of their transcriptomic and phylogenetic analyses is more nuanced than explained in the paper. For example, the authors didn't explain in sufficient detail how the data summary in Fig. 5 "demonstrate" that the epidermal thread cells are "ancestral", and that the diversity of alpha and gamma thread biopolymer genes is a prerequisite to slime (without a functional analysis), or that the gene duplication events facilitated the origin of hagfish slime.
This work stands unique. I am not aware of any other study that attempted to explain the origin of this truly bewildering adaptation in hagfish with such a multifaceted approach.
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Reviewer #2 (Public Review):
The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. I appreciate the careful and detailed measurements and images that the authors provide. The results presented here will surely be extremely important for researchers working on this particular organism and those interested in understanding the evolution, biomedical relevance, and biochemistry of mucus. However, I had difficulty contextualizing the findings in broader biological questions (e.g., the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution). I also think that the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative …
Reviewer #2 (Public Review):
The study is a careful investigation of the physical properties of hagfish slime and the underlying cellular framework that enables this extraordinary evolutionary innovation. I appreciate the careful and detailed measurements and images that the authors provide. The results presented here will surely be extremely important for researchers working on this particular organism and those interested in understanding the evolution, biomedical relevance, and biochemistry of mucus. However, I had difficulty contextualizing the findings in broader biological questions (e.g., the evolution of functional novelty, the adaptive processes, and the links between genetic and phenotypic evolution). I also think that the conclusions on the evolutionary origins and underlying genetics of hagfish slime based on comparative transcriptomic data may be premature.
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