Studies of Turing pattern formation in zebrafish skin Kondo, Shigeru; Watanabe, Masakatsu; Miyazawa, Seita
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
12/2021, Volume:
379, Issue:
2213
Journal Article
Peer reviewed
Open access
Skin patterns are the first example of the existence of Turing patterns in living organisms. Extensive research on zebrafish, a model organism with stripes on its skin, has revealed the principles of ...pattern formation at the molecular and cellular levels. Surprisingly, although the networks of cell-cell interactions have been observed to satisfy the 'short-range activation and long-range inhibition' prerequisites for Turing pattern formation, numerous individual reactions were not envisioned based on the classical reaction-diffusion model. For example, in real skin, it is not an alteration in concentrations of chemicals, but autonomous migration and proliferation of pigment cells that establish patterns, and cell-cell interactions are mediated via direct contact through cell protrusions. Therefore, the classical reaction-diffusion mechanism cannot be used as it is for modelling skin pattern formation. Various studies are underway to adapt mathematical models to the experimental findings on research into skin patterns, and the purpose of this review is to organize and present them. These novel theoretical methods could be applied to autonomous pattern formation phenomena other than skin patterns. This article is part of the theme issue 'Recent progress and open frontiers in Turing's theory of morphogenesis'.
Gap junctions are intercellular channels that allow passage of ions and small molecules between adjacent cells. Gap junctions in vertebrates are composed of connexons, which are an assembly of six ...proteins, connexins. Docking of two connexons on the opposite cell surfaces forms a gap junction between the cytoplasm of two neighboring cells. Connexins compose a family of structurally related four-pass transmembrane proteins. In mammals, there are ~20 connexins, each of which contributes to unique permeability of gap junctions, and mutations of some connexin-encoding genes are associated with human diseases. Zebrafish has been predicted to contain 39 connexin-encoding genes; the high number can be attributed to gene duplication during fish evolution, which resulted in diversified functions of gap junctions in teleosts. The determination of body shapes and skin patterns in animal species is an intriguing question. Mathematical models suggest principle mechanisms explaining the diversification of animal morphology. Recent studies have revealed the involvement of gap junctions in fish morphological diversity, including skin pattern formation and body shape determination. This review focuses on connexins in teleosts, which are integrated in the mathematical models explaining morphological diversity of animal skin patterns and body shapes.
Connexin39.4 (Cx39.4) and Connexin41.8 (Cx41.8), two gap-junction proteins expressed in both melanophores and xanthophores, are critical for the intercellular communication among pigment cells that ...is necessary for generating the stripe pigment pattern of zebrafish. We previously characterized the gap-junction properties of Cx39.4 and Cx41.8, but how these proteins contribute to stripe formation remains unclear; this is because distinct types of connexins potentially form heteromeric gap junctions, which precludes accurate elucidation of individual connexin functions in vivo. Here, by arranging Cx39.4 and Cx41.8 expression in pigment cells, we identified the simplest gap-junction network required for stripe generation: Cx39.4 expression in melanophores is required but expression in xanthophores is not necessary for stripe patterning, whereas Cx41.8 expression in xanthophores is sufficient for the patterning, and Cx41.8 expression in melanophores might stabilize the stripes. Moreover, patch-clamp recordings revealed that Cx39.4 gap junctions exhibit spermidine-dependent rectification property. Our results suggest that Cx39.4 facilitates the critical cell-cell interactions between melanophores and xanthophores that mediate a unidirectional activation-signal transfer from xanthophores to melanophores, which is essential for melanophore survival.
Mahalwar
et al
. (Reports, 12 September 2014, p. 1362) observed the onset of pigment pattern formation in zebrafish. They concluded that their data do not support our Turing mechanism–based model and ...presented an essentially different mechanism. Here, we clarify their misunderstanding that may have caused their conclusion and explain past experimental data that do not support their proposed mechanism.
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Scoliosis is a condition where the spine curves sideways, unique to humans due to their upright posture. However, the cause of this disease is not well understood because it is challenging to find a ...model for experimentation. This study aimed to create a model for human idiopathic scoliosis by manipulating the function of mechanosensitive channels called Piezo channels in zebrafish. Zebrafish were chosen because they experience similar biomechanical forces to humans, particularly in relation to the role of mechanical force in scoliosis progression. Here we describe
and
are involved in bone formation, with a double knockout resulting in congenital systemic malformations. However, an in-frame mutation of
led to fully penetrant juvenile-onset scoliosis, bone asymmetry, reduced tissue mineral density, and abnormal intervertebral discs-resembling non-congenital scoliosis symptoms in humans. These findings suggest that functional Piezo channels responding to mechanical forces are crucial for bone formation and maintaining spine integrity, providing insights into skeletal disorders.
Although domesticated goldfish strains exhibit highly diversified phenotypes in morphology, the genetic basis underlying these phenotypes is poorly understood. Here, based on analysis of transposable ...elements in the allotetraploid goldfish genome, we found that its two subgenomes have evolved asymmetrically since a whole-genome duplication event in the ancestor of goldfish and common carp. We conducted whole-genome sequencing of 27 domesticated goldfish strains and wild goldfish. We identified more than 60 million genetic variations and established a population genetic structure of major goldfish strains. Genome-wide association studies and analysis of strain-specific variants revealed genetic loci associated with several goldfish phenotypes, including dorsal fin loss, long-tail, telescope-eye, albinism, and heart-shaped tail. Our results suggest that accumulated mutations in the asymmetrically evolved subgenomes led to generation of diverse phenotypes in the goldfish domestication history. This study is a key resource for understanding the genetic basis of phenotypic diversity among goldfish strains.
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•The goldfish genome was partitioned into two asymmetrically evolved subgenomes•Wild goldfish and 27 goldfish strains were genetically classified into three groups•Six genetic loci associated with five goldfish phenotypes were newly determined•Asymmetrically evolved subgenomes seem to generate diverse goldfish phenotypes
Kon et al. provide genome-wide evidence of evolution and diversity of goldfish. Three groups were identified based on domestication history. Six genetic loci associated with five goldfish phenotypes are described, showing that differential evolution of subgenomes in goldfish is likely to have contributed to the diversity of goldfish phenotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
The skin patterns of animals are very important for their survival, yet the mechanisms involved in skin pattern formation remain unresolved. Turing’s reaction–diffusion model presents a ...well‐known mathematical explanation of how animal skin patterns are formed, and this model can predict various animal patterns that are observed in nature. In this study, we used transgenic zebrafish to generate various artificial skin patterns including a narrow stripe with a wide interstripe, a narrow stripe with a narrow interstripe, a labyrinth, and a ‘leopard’ pattern (or donut‐like ring pattern). In this process, connexin41.8 (or its mutant form) was ectopically expressed using the mitfa promoter. Specifically, the leopard pattern was generated as predicted by Turing’s model. Our results demonstrate that the pigment cells in animal skin have the potential and plasticity to establish various patterns and that the reaction–diffusion principle can predict skin patterns of animals.
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The skin pigment pattern of zebrafish is a good model system in which to study the mechanism of biological pattern formation. Although it is known that interactions between melanophores and ...xanthophores play a key role in the formation of adult pigment stripes, molecular mechanisms for these interactions remain largely unknown. Here, we show that Delta/Notch signaling contributes to these interactions. Ablation of xanthophores in yellow stripes induced the death of melanophores in black stripes, suggesting that melanophores require a survival signal from distant xanthophores. We found that deltaC and notch1a were expressed by xanthophores and melanophores, respectively. Moreover, inhibition of Delta/Notch signaling killed melanophores, whereas activation of Delta/Notch signaling ectopically in melanophores rescued the survival of these cells, both in the context of pharmacological inhibition of Delta/Notch signaling and after ablation of xanthophores. Finally, we showed by in vivo imaging of cell membranes that melanophores extend long projections towards xanthophores in the yellow stripes. These data suggest that Delta/Notch signaling is responsible for a survival signal provided by xanthophores to melanophores. As cellular projections can enable long-range interaction between membrane-bound ligands and their receptors, we propose that such projections, combined with direct cell-cell contacts, can substitute for the effect of a diffusible factor that would be expected by the conventional reaction-diffusion (Turing) model.
Pannexin (PANX) family proteins form large-pore channels that mediate purinergic signaling. We analyzed the cryo-EM structures of human PANX1 in lipid nanodiscs to elucidate the gating mechanism and ...its regulation by the amino terminus in phospholipids. The wild-type channel has an amino-terminal funnel in the pore, but in the presence of the inhibitor probenecid, a cytoplasmically oriented amino terminus and phospholipids obstruct the pore. Functional analysis using whole-cell patch-clamp and oocyte voltage clamp showed that PANX1 lacking the amino terminus did not open and had a dominant negative effect on channel activity, thus confirming that the amino-terminal domain played an essential role in channel opening. These observations suggest that dynamic conformational changes in the amino terminus of human PANX1 are associated with lipid movement in and out of the pore. Moreover, the data provide insight into the gating mechanism of PANX1 and, more broadly, other large-pore channels.
Connexin 39.4 (Cx39.4) is involved in zebrafish (Danio rerio) skin patterning; when mutated, zebrafish exhibit a wavy stripe/labyrinth pattern instead of stripes. Cx39.4 is unique in that it has two ...additional serine/arginine (SR) residues, Ser2 and Arg3, at positions 2 and 3. Here, I investigated the role of these SR residues in Cx39.4 function.
To examine the SR residues in Cx39.4, mutants of the SR residues were generated. Voltage-clamp recordings were performed using Xenopus oocytes to characterize the channel properties of the mutants. Transgenic zebrafish expressing each mutant were generated, and the effects of each mutation on fish skin patterning were evaluated.
The Cx39.4R3K mutant showed essentially the same properties as the wild-type (Cx39.4WT) in both electrophysiological analyses, leading to transgenic, complete phenotype rescue. Both the Cx39.4R3A mutant and deletion mutant of SR residues (Cx39.4delSR) showed a faster decay of gap junction activity and abnormal hemichannel activity, resulting in wide stripes and interstripes that indicate instability. Although the Cx39.4R3D mutant showed no channel activity in gap junctions or hemichannels, it caused unstable phenotypes in the transgene, namely a completely rescued phenotype in some individuals and loss of melanophores in others.
The SR residues in the NT domain of Cx39.4 are critical for the regulation of channel function, which appears to determine skin patterning.
These results elucidate the roles of the two SR residues unique to the NT domain of Cx39.4 in its channel function, which is important for zebrafish stripe pattern formation.
•We investigated role of serine/arginine (SR) residues in Cx39.4 function in zebrafish.•Voltage-clamp recordings in Xenopus oocytes were used to analyze SR residues in Cx39.4.•SR residues are critical for channel function and may affect skin patterning.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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