The ABC transporter Snu drives formation of the lipid-based inward and outward barrier in the skin of Drosophila

AbstractLipids in extracellular matrices (ECM) contribute to barrier function and stability of epithelial tissues such as the pulmonary alveoli and the skin. In insects, skin waterproofness depends on the outermost layer of the extracellular cuticle termed envelope that contains cuticulin, an unidentified water-repellent complex molecule composed of proteins, lipids and catecholamines. Based on live-imaging analyses of fruit fly larvae, we find that initially envelope units are assembled within vesicles harbouring the ABC transporter Snu and the extracellular protein Snsl. In a second step, the content of these vesicles is distributed to cuticular lipid-transporting nanotubes named pore canals and to the cuticle surface in dependence of Snu function. Consistently, the surface of snu and snsl mutant larvae is depleted from lipids and cuticulin. By consequence, these animals suffer uncontrolled water loss and penetration of xenobiotics. Our data allude to a two-step model of envelope i.e. barrier formation. The proposed mechanism in principle parallels the events occurring during differentiation of the lipid-based ECM by keratinocytes in the vertebrate skin suggesting establishment of analogous mechanisms of skin barrier formation in vertebrates and invertebrates.

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Dysfunction of Torr causes a Harlequin-type ichthyosis-like phenotype in Drosophila melanogaster

10.1101/734400 ◽

2019 ◽

Author(s):

Y Wang ◽

M Norum ◽

K Oehl ◽

Y Yang ◽

R Zuber ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Cuticular Hydrocarbons ◽

Abc Transporter ◽

Water Loss ◽

Molecular Mechanisms ◽

Fruit Fly ◽

Skin Surface ◽

Barrier Formation ◽

Pore Canals ◽

And Function

AbstractPrevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Torr - a human ABCA12 paralog - contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Torr function provokes rapid desiccation. Torr is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Torr activity is reduced. GFP-tagged Torr localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Torr is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in torr mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Torr and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The torr deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved in vertebrates in invertebrates.Author SummaryAs in humans, lipids on the surface of the skin of insects protect the organism against excessive water loss and penetration of potentially harmful substances. During evolution, a greasy surface was indeed an essential trait for adaptation to life outside a watery environment. Here, we show that the membrane-gate transporter Torr is needed for the deposition of barrier lipids on the skin surface in the fruit fly Drosophila melanogaster through extracellular nano-tubes, called pore canals. In principle, the involvement of Torr parallels the scenario in humans, where the membrane-gate transporter ABCA12 is implicated in the construction of the lipid-based stratum corneum of the skin. In both cases, mutations in the genes coding for the respective transporter cause rapid water-loss and are lethal soon after birth. We conclude that the interaction between the organism and the environment obviously implies an analogous mechanism of barrier formation and function in vertebrates and invertebrates.

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Faculty Opinions recommendation of TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4568992.4439101 ◽

2010 ◽

Author(s):

Richard Anderson ◽

Yue Sun

Keyword(s):

Skin Barrier ◽

Trp Channel ◽

Egfr Signaling ◽

Barrier Formation ◽

Hair Morphogenesis

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Temporally controlled targeted somatic mutagenesis in embryonic surfaceectoderm and fetal epidermal keratinocytes unveils two distinct developmentalfunctions of BRG1 in limb morphogenesis and skin barrier formation

Development ◽

10.1242/dev.02019 ◽

2005 ◽

Vol 132 (20) ◽

pp. 4533-4544 ◽

Cited By ~ 79

Author(s):

A. K. Indra ◽

V. Dupe ◽

J.-M. Bornert ◽

N. Messaddeq ◽

M. Yaniv ◽

...

Keyword(s):

Skin Barrier ◽

Epidermal Keratinocytes ◽

Barrier Formation ◽

Limb Morphogenesis ◽

Somatic Mutagenesis

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Transdisciplinary Aspects of Morphological Productivity

European Review ◽

10.1017/s1062798708000331 ◽

2008 ◽

Vol 16 (4) ◽

pp. 457-466

Author(s):

Wolfgang U. Dressler

Keyword(s):

Language Acquisition ◽

First Language ◽

Word Formation ◽

Second Step ◽

First Language Acquisition ◽

Step Model ◽

Morphological Productivity ◽

Rule Application ◽

Online Tests

This contribution presents a model of morphological productivity that allows some points of comparison with the concept of productivity in economics and in other disciplines. It is a two-step model: in the first step, degrees of productivity of morphological rules are established on the so-called syntagmatic axis of language, i.e. how a word is changed in its linear make-up, e.g. English boy becomes boy-s in the plural or is changed to boy-friend, boy-hood, boy-ish in word formation. In the second step, rule application is compared on the so-called paradigmatic axis with possibly competing productive rules, e.g. in adjective formation from nouns, suffixation with -ish (e.g. boy-ish), is compared with suffixations with -y (e.g. fier-y), -ly (e.g. friend-ly), -ic (e.g. syntact-ic), -ical (e.g. morpholog-ical). Then supportive psycholinguistic evidence is presented from online tests and first language acquisition, an area of crucial evidence for linguistic theories, since any constructs of a model must be learnable by children.

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Keratinocyte-Specific Ablation of RIPK4 Allows Epidermal Cornification but Impairs Skin Barrier Formation

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.12.031 ◽

2018 ◽

Vol 138 (6) ◽

pp. 1268-1278 ◽

Cited By ~ 8

Author(s):

Corinne Urwyler-Rösselet ◽

Giel Tanghe ◽

Kirsten Leurs ◽

Barbara Gilbert ◽

Riet De Rycke ◽

...

Keyword(s):

Skin Barrier ◽

Barrier Formation

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Skin permeability barrier formation by the ichthyosis-causative gene FATP4 through formation of the barrier lipid ω-O-acylceramide

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1917525117 ◽

2020 ◽

Vol 117 (6) ◽

pp. 2914-2922 ◽

Cited By ~ 6

Author(s):

Haruka Yamamoto ◽

Miku Hattori ◽

Walee Chamulitrat ◽

Yusuke Ohno ◽

Akio Kihara

Keyword(s):

Skin Barrier ◽

Human Keratinocytes ◽

Skin Permeability ◽

Permeability Barrier ◽

Barrier Dysfunction ◽

Causative Gene ◽

Synthetic Pathway ◽

Barrier Formation ◽

Chain Lengths

The epidermis-specific lipid acylceramide plays a pivotal role in the formation of the permeability barrier in the skin; abrogation of its synthesis causes the skin disorder ichthyosis. However, the acylceramide synthetic pathway has not yet been fully elucidated: Namely, the acyl-CoA synthetase (ACS) involved in this pathway remains to be identified. Here, we hypothesized it to be encoded by FATP4/ACSVL4, the causative gene of ichthyosis prematurity syndrome (IPS). In vitro experiments revealed that FATP4 exhibits ACS activity toward an ω-hydroxy fatty acid (FA), an intermediate of the acylceramide synthetic pathway. Fatp4 knockout (KO) mice exhibited severe skin barrier dysfunction and morphological abnormalities in the epidermis. The total amount of acylceramide in Fatp4 KO mice was reduced to ∼10% of wild-type mice. Decreased levels and shortening of chain lengths were observed in the saturated, nonacylated ceramides. FA levels were not decreased in the epidermis of Fatp4 KO mice. The expression levels of the FA elongase Elovl1 were reduced in Fatp4 KO epidermis, partly accounting for the reduction and shortening of saturated, nonacylated ceramides. A decrease in acylceramide levels was also observed in human keratinocytes with FATP4 knockdown. From these results, we conclude that skin barrier dysfunction observed in IPS patients and Fatp4 KO mice is caused mainly by reduced acylceramide production. Our findings further elucidate the molecular mechanism governing acylceramide synthesis and IPS pathology.

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