DOI: 10.1111/exd.12408 www.wileyonlinelibrary.com/journal/EXD
Commentary from the Editorial Board
Deadly hairs, lethal feathers – convergent evolution of poisonous integument in mammals and birds Maksim V. Plikus1 and Aliaksandr A. Astrowski2 1
Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA; Department of Medical Biology and Genetics, Grodna State Medical University, Grodna, Belarus Correspondence: Maksim V. Plikus, PhD, Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA, Tel.: +949-824-1260, Fax: +949-824-4709, e-mail: [email protected] 2
Abstract: Hairs and feathers are textbook examples of the convergent evolution of the follicular appendage structure between mammals and birds. While broadly recognized for their convergent thermoregulatory, camouflage and sexual display functions, hairs and feathers are rarely thought of as deadly defence tools. Several recent studies, however, show that in some species of mammals and birds, the integument can, in fact, be a de facto lethal weapon. One mammalian example is provided by African crested rats, which seek for and chew on the bark of plants containing the highly potent toxin, ouabain. These rats then coat their fur with ouabain-containing saliva. For efficient toxin retention, the rodents have evolved highly specialized fenestrated and mostly hollow hair shafts that soak up liquids, which essentially function as wicks. On the avian side of the vertebrate integumental variety spectrum, several species of birds of New Guinea have evolved resistance to
highly potent batrachotoxins, which they acquire from their insect diet. While the mechanism of bird toxicity remains obscure, in a recently published issue of the journal, Dumbacher and Menon explore the intriguing idea that to achieve efficient storage of batrachotoxins in their skin, some birds exploit the basic permeability barrier function of their epidermis. Batrachotoxins become preferentially sequestered in their epidermis and are then transferred to feathers, likely through the exploitation of specialized avian lipid-storing multigranular body organelles. Here, we discuss wider implications of this intriguing concept.
Toxicity is rarely thought of as a feature of mammalian and avian defence systems. However, several recent studies highlight that toxic species indeed exist in both vertebrate classes. In general, animals are considered toxic if they are able to produce or accumulate exogenous substances that can cause pathological reactions, including rapidly evolving disease or even death of their prey or predators. Toxic animals can be broadly classified into two categories – those that are able to produce their own toxins and those that acquire toxins from their environment while maintaining relative resistance to the toxin’s poisonous effects. Some species passively accumulate toxic metabolites, while others actively produce venom, often in specialized venom glands. Many of the actively venomous species have also evolved means for efficient delivery of the venom, such as via stings, needles and fangs. It turns out that mammalian species can be identified in nearly all of these categories (1,2), while several species of birds have evolved an acquired toxicity (3–5). Among mammals, several species of shrews, including European water shrew, Mediterranean water shrew and northern short-tailed shrew, are known to have venom-producing salivary glands. Venomous saliva coats the inner surface of their incisors and is delivered with the bite. In the laboratory setting, blarina toxin extracted from northern short-tailed shrews causes paralysis, convulsions and death in mice (6). In the same order with venomous shrews are the Hispaniolan and Cuban solenodons, which in addition to venomous salivary glands, have evolved a specialized dental venom delivery system, similar to venomous snakes. Their salivary glands are connected to second man-
dibular incisors featuring deep grooves in which toxin is transmitted with the bite (2). Active venomousness, like that of modern day shrews and solenodons, has been considered to be fairly common among prehistoric mammals. Newly emerging paleontological evidence has shown that dental venom delivery has existed in extinct shrews (7) and at least in one other extinct order of Cimolesta (8). Curiously, specialized venom delivery systems have evolved independently of the dental transmission mechanism in the integument of platypus, one of the only five extant species of egg-laying mammals from the order of Monotremata (along with four species of Echidna). Platypus and echidna have homologous crural/femoral glands connected by a duct to the keratinous spur on their hind limb (9). While echidna glands and spurs are not well defined, platypus femoral glands produce a complex set of toxins that can be injected via the opening at the spur’s tip (10,11). Femoral gland activity is distinctly seasonal, with the peak during spring breeding season. It is thought that seasonal venomousness in platypus is used to fight off other males during territorial disputes; however, their venom produces complex toxic reactions in other species, including humans (12). Paleontological evidence suggests that venomous crural gland-spur apparati were rather common integument derivatives in ancestral mammals and subsequently became lost in modern day mammals with the exception of Monotremata (13,14). Can other appendages of mammalian integument aid in toxicity? A recent study by Kingdon and Agwanda (15) reveals a series of peculiar adaptations that allow African crested rats to store a
466
Key words: feather – gland – hair follicle – integument – venom
Accepted for publication 30 March 2014
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
Commentary from the Editorial Board
(a)
(b)
(c)
Figure 1. Hair of African crested rats. (a) African crested rat with poison hair tract exposed (credit: Creative Commons). (b) Demonstration of the wicking effects of the African crested rat hair using red ink over 30 s (15). (c) False-coloured scanning electron microscopy of poison tract hair showing fenestrated cortex and medullary trabeculae (credit: Fritz Vollrath).
deadly toxin in their hair and use it as part of their defence strategy against predators. African crested rats have evolved highly specialized and unusual hairs located along the lateral tract on their flank (Fig. 1a). Scanning electron microscopy reveals that instead of being solid, like hairs of mice and humans, African crested rat hairs are hollow on the inside and mostly lack cuticle. Moreover, their cortex is fenestrated and mesh like, and the hollow centre contains many thin medullary trabeculae (Fig. 1c) (15,16). These features come together to essentially convert the hairs into highly absorbent wicks – a truly marvellous feat of biological engineering. When submerged in coloured ink, these porous hairs can be seen soaking up the liquid (Fig. 1b). African crested rats use this feature to saturate their hairs with saliva while chewing on the bark of Acokanthera schimperi, an abundant plant in their habitat. Curiously, the bark of this plant contains highly toxic ouabain. For centuries, these plants were used for making poisonous arrows, potent enough to kill an elephant (15). Normally, poisonous hairs of the lateral tract are covered by much longer hairs growing along the spine. However, when threatened, rats take on a defensive posture and lift their long hairs using specialized dermal muscles to uncover the poisonous fur patch. The amount of poison that hairs can carry suffices to kill a dog. Interestingly, coating hairs with poison as an adaptive behavioural strategy is not unique to African crested rats. Some hedgehog species, such as Atelerix pruneri and Hemiechinus Auritus, have prominent self-anointing behaviour; they chew on the skin and parotid glands of the toads they prey on and slather poisonous glandular secretion onto their spines (17). In that sense, hedgehogs can be said to be both armoured (with their spines) and poisonous mammals. Wick-like hairs of African crested rats are also fascinating from the point of view of hair biology. It remains a mystery how the proliferation and differentiation events at the base of the anagen
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
Figure 2. Diversity of hair shapes. On a cross-section, platypus’ hair looks like a knife blade, alpine pika’s hair like a dog bone, and Linnaeus’s two-toed sloth’s hair like a cloud bubble (Photographs credit: Creative Commons; scanning electron microscopy credit: Olga Chernova).
hair follicle lead to the formation of such an intricate micro-anatomical structures. This example also highlights the fact that there is more to hairs than just their functions as a solid fibre. Indeed, hairs in many mammalian species have complex shapes. On a cross-section, hairs look like a knife blade in platypus, like a dog bone in alpine pika and like a cloud bubble in Linnaeus’s twotoed sloth (5) (Fig. 2). Similar to that of African crested rats, hairs in many other mammals have porous and cavernous medulla, and the detailed classification provided by Chernova (18) underscores the fascinating breadth of morphological polymorphism of hair. While rare among Aves, at least five species of birds, that is, three members of genus Pitohui, blue-capped Ifrita and Rufous Shrikethrush, have been confirmed to have evolved an acquired toxicity, thus documenting that integument-associated toxicity spans a very wide spectrum of vertebrate skin phenotypes and reaches way back in vertebrate evolution. The skin and feathers of these birds accumulate batrachotoxins, steroidal alkaloids with extremely potent cardio- and neurotoxic properties. Interestingly, this represents the same type of toxins that are found in the skin of so-called poison dart frogs (3,4). Endemic to New Guinea, Pitohui birds can cause irritation of mucosal membranes and eyes, as well as skin numbness when handled with bare hands (3,19). In a prominent example of convergent evolution, it is thought that Pitohui and Ifrita acquire their toxicity in the same way poison dart frogs do – by consuming batrachotoxins-containing insects (20). In turn, insects are
467
Commentary from the Editorial Board
presumed to produce batrachotoxins from phytosterols of the plants on which they feed. While the mechanisms of bird toxicity remain obscure, in a recently published issue of the journal, Menon and Dumbacher (5) explore an intriguing idea that to achieve efficient storage of batrachotoxins in their skin and feathers, Pitohui exploit the basic permeability barrier function of their epidermis. Unlike most mammals, birds in general have very thin epidermis, and their keratinocytes produce large organelles called multigranular bodies (MGB). As they mature, MGBs convert to neutral lipid droplets that maintain droplet organization and thus efficiently retain their content upon terminal differentiation of keratinocytes. Building upon the fact that the presence of toxic alkaloids in plant cells and cutaneous gland cells in poison dart frogs strongly correlates with selective osmiophilia on electron microscopy, Menon and Dumbacher (5) showed that, in comparison with non-poisonous avian species, MGBs in Pitohui epidermis are highly osmiophilic. This osmiophilia, and likely alkaloid accumulation, is selective to MGBs, suggesting that Pitohui have an active mechanism for batrachotoxins sequestration in their epidermal keratinocytes. It remains unclear how batrachotoxins incorporate into feather, which in Pitohui are just as toxic as the skin. Curiously, the oily
secretion from the uropygial gland, which birds commonly apply onto their plumage to maintain the feather’s integrity and function, can be ruled out as a significant source of batrachotoxins. In experiments, concentrated ethanol extracts of Pitohui skin and feathers, but not of the uropygial gland, have caused convulsions and quick death upon subcutaneous injection into mice (3). Taken together, the recent work by Menon and Dumbacher (5) and Kingdon and Agwanda (15) underscores the fact that skin and its various appendages in both birds and mammals can become efficient and often deadly defence tools. Moreover, it highlights that poisonousness is a common convergent evolutionary strategy that has become embedded into the complexity of vertebrate skin phenotypes.
Acknowledgements M.V.P. is supported by a Edward Mallinckrodt Jr. Foundation Research Grant and a Dermatology Foundation Research Grant. M.V.P. conceived and wrote the commentary. A.A.A. provided critical conceptual advice and assisted with writing. The authors are thankful to Dr. Fritz Vollrath and Dr. Olga Chernova for graciously permitting to reproduce their images.
Conflict of Interest The authors have declared no conflict of interest.
References 1 Ligabue-Braun R, Verli H, Carlini C R. Toxicon 2012: 59: 680–695. 2 Dufton M J. Pharmacol Ther 1992: 53: 199–215. 3 Dumbacher J P, Beehler B M, Spande T F et al. Science 1992: 258: 799–801. 4 Dumbacher J P, Spande T F, Daly J W. Proc Natl Acad Sci USA 2000: 97: 12970–12975. 5 Menon G K, Dumbacher J P. Exp Dermatol 2014: 23: 288–290. 6 Kita M, Nakamura Y, Okumura Y et al. Proc Natl Acad Sci USA 2004: 101: 7542–7547. 7 Cuenca-Bescos G, Rofes J. Naturwissenschaften 2007: 94: 113–116.
468
8 Fox R C, Scott C S. Nature 2005: 435: 1091– 1093. 9 Krause W J. Cells, Tissues, Organs 2010: 191: 336–354. 10 Whittington C M, Papenfuss A T, Locke D P et al. Genome Biol 2010: 11: R95. 11 Whittington C M, Koh J M, Warren W C et al. J proteomics 2009: 72: 155–164. 12 Fenner P J, Williamson J A, Myers D. Med J Aust 1992: 157: 829–832. 13 Li G, Luo Z X. Nature 2006: 439: 195–200. 14 Hu Y, Wang Y, Luo Z et al. Nature 1997: 390: 137–142.
15 Kingdon J, Agwanda B, Kinnaird M et al. Proc Biol Sci 2012: 279: 675–680. 16 Stoddart D M. J Zool 1979: 189: 551–553. 17 Brodie E D. Nature 1977: 268: 627–628. 18 Chernova O F. Izv Akad Nauk Ser Biol 2003: 1: 63–73. 19 Diamond J M. Nature 1992: 360: 19–20. 20 Dumbacher J P, Wako A, Derrickson S R et al. Proc Natl Acad Sci USA 2004: 101: 15857–15860.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
Commentary from the Editorial Board
Deadly hairs, lethal feathers – convergent evolution of poisonous integument in mammals and birds Maksim V. Plikus1 and Aliaksandr A. Astrowski2 1
Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA; Department of Medical Biology and Genetics, Grodna State Medical University, Grodna, Belarus Correspondence: Maksim V. Plikus, PhD, Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA, Tel.: +949-824-1260, Fax: +949-824-4709, e-mail: [email protected] 2
Abstract: Hairs and feathers are textbook examples of the convergent evolution of the follicular appendage structure between mammals and birds. While broadly recognized for their convergent thermoregulatory, camouflage and sexual display functions, hairs and feathers are rarely thought of as deadly defence tools. Several recent studies, however, show that in some species of mammals and birds, the integument can, in fact, be a de facto lethal weapon. One mammalian example is provided by African crested rats, which seek for and chew on the bark of plants containing the highly potent toxin, ouabain. These rats then coat their fur with ouabain-containing saliva. For efficient toxin retention, the rodents have evolved highly specialized fenestrated and mostly hollow hair shafts that soak up liquids, which essentially function as wicks. On the avian side of the vertebrate integumental variety spectrum, several species of birds of New Guinea have evolved resistance to
highly potent batrachotoxins, which they acquire from their insect diet. While the mechanism of bird toxicity remains obscure, in a recently published issue of the journal, Dumbacher and Menon explore the intriguing idea that to achieve efficient storage of batrachotoxins in their skin, some birds exploit the basic permeability barrier function of their epidermis. Batrachotoxins become preferentially sequestered in their epidermis and are then transferred to feathers, likely through the exploitation of specialized avian lipid-storing multigranular body organelles. Here, we discuss wider implications of this intriguing concept.
Toxicity is rarely thought of as a feature of mammalian and avian defence systems. However, several recent studies highlight that toxic species indeed exist in both vertebrate classes. In general, animals are considered toxic if they are able to produce or accumulate exogenous substances that can cause pathological reactions, including rapidly evolving disease or even death of their prey or predators. Toxic animals can be broadly classified into two categories – those that are able to produce their own toxins and those that acquire toxins from their environment while maintaining relative resistance to the toxin’s poisonous effects. Some species passively accumulate toxic metabolites, while others actively produce venom, often in specialized venom glands. Many of the actively venomous species have also evolved means for efficient delivery of the venom, such as via stings, needles and fangs. It turns out that mammalian species can be identified in nearly all of these categories (1,2), while several species of birds have evolved an acquired toxicity (3–5). Among mammals, several species of shrews, including European water shrew, Mediterranean water shrew and northern short-tailed shrew, are known to have venom-producing salivary glands. Venomous saliva coats the inner surface of their incisors and is delivered with the bite. In the laboratory setting, blarina toxin extracted from northern short-tailed shrews causes paralysis, convulsions and death in mice (6). In the same order with venomous shrews are the Hispaniolan and Cuban solenodons, which in addition to venomous salivary glands, have evolved a specialized dental venom delivery system, similar to venomous snakes. Their salivary glands are connected to second man-
dibular incisors featuring deep grooves in which toxin is transmitted with the bite (2). Active venomousness, like that of modern day shrews and solenodons, has been considered to be fairly common among prehistoric mammals. Newly emerging paleontological evidence has shown that dental venom delivery has existed in extinct shrews (7) and at least in one other extinct order of Cimolesta (8). Curiously, specialized venom delivery systems have evolved independently of the dental transmission mechanism in the integument of platypus, one of the only five extant species of egg-laying mammals from the order of Monotremata (along with four species of Echidna). Platypus and echidna have homologous crural/femoral glands connected by a duct to the keratinous spur on their hind limb (9). While echidna glands and spurs are not well defined, platypus femoral glands produce a complex set of toxins that can be injected via the opening at the spur’s tip (10,11). Femoral gland activity is distinctly seasonal, with the peak during spring breeding season. It is thought that seasonal venomousness in platypus is used to fight off other males during territorial disputes; however, their venom produces complex toxic reactions in other species, including humans (12). Paleontological evidence suggests that venomous crural gland-spur apparati were rather common integument derivatives in ancestral mammals and subsequently became lost in modern day mammals with the exception of Monotremata (13,14). Can other appendages of mammalian integument aid in toxicity? A recent study by Kingdon and Agwanda (15) reveals a series of peculiar adaptations that allow African crested rats to store a
466
Key words: feather – gland – hair follicle – integument – venom
Accepted for publication 30 March 2014
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
Commentary from the Editorial Board
(a)
(b)
(c)
Figure 1. Hair of African crested rats. (a) African crested rat with poison hair tract exposed (credit: Creative Commons). (b) Demonstration of the wicking effects of the African crested rat hair using red ink over 30 s (15). (c) False-coloured scanning electron microscopy of poison tract hair showing fenestrated cortex and medullary trabeculae (credit: Fritz Vollrath).
deadly toxin in their hair and use it as part of their defence strategy against predators. African crested rats have evolved highly specialized and unusual hairs located along the lateral tract on their flank (Fig. 1a). Scanning electron microscopy reveals that instead of being solid, like hairs of mice and humans, African crested rat hairs are hollow on the inside and mostly lack cuticle. Moreover, their cortex is fenestrated and mesh like, and the hollow centre contains many thin medullary trabeculae (Fig. 1c) (15,16). These features come together to essentially convert the hairs into highly absorbent wicks – a truly marvellous feat of biological engineering. When submerged in coloured ink, these porous hairs can be seen soaking up the liquid (Fig. 1b). African crested rats use this feature to saturate their hairs with saliva while chewing on the bark of Acokanthera schimperi, an abundant plant in their habitat. Curiously, the bark of this plant contains highly toxic ouabain. For centuries, these plants were used for making poisonous arrows, potent enough to kill an elephant (15). Normally, poisonous hairs of the lateral tract are covered by much longer hairs growing along the spine. However, when threatened, rats take on a defensive posture and lift their long hairs using specialized dermal muscles to uncover the poisonous fur patch. The amount of poison that hairs can carry suffices to kill a dog. Interestingly, coating hairs with poison as an adaptive behavioural strategy is not unique to African crested rats. Some hedgehog species, such as Atelerix pruneri and Hemiechinus Auritus, have prominent self-anointing behaviour; they chew on the skin and parotid glands of the toads they prey on and slather poisonous glandular secretion onto their spines (17). In that sense, hedgehogs can be said to be both armoured (with their spines) and poisonous mammals. Wick-like hairs of African crested rats are also fascinating from the point of view of hair biology. It remains a mystery how the proliferation and differentiation events at the base of the anagen
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
Figure 2. Diversity of hair shapes. On a cross-section, platypus’ hair looks like a knife blade, alpine pika’s hair like a dog bone, and Linnaeus’s two-toed sloth’s hair like a cloud bubble (Photographs credit: Creative Commons; scanning electron microscopy credit: Olga Chernova).
hair follicle lead to the formation of such an intricate micro-anatomical structures. This example also highlights the fact that there is more to hairs than just their functions as a solid fibre. Indeed, hairs in many mammalian species have complex shapes. On a cross-section, hairs look like a knife blade in platypus, like a dog bone in alpine pika and like a cloud bubble in Linnaeus’s twotoed sloth (5) (Fig. 2). Similar to that of African crested rats, hairs in many other mammals have porous and cavernous medulla, and the detailed classification provided by Chernova (18) underscores the fascinating breadth of morphological polymorphism of hair. While rare among Aves, at least five species of birds, that is, three members of genus Pitohui, blue-capped Ifrita and Rufous Shrikethrush, have been confirmed to have evolved an acquired toxicity, thus documenting that integument-associated toxicity spans a very wide spectrum of vertebrate skin phenotypes and reaches way back in vertebrate evolution. The skin and feathers of these birds accumulate batrachotoxins, steroidal alkaloids with extremely potent cardio- and neurotoxic properties. Interestingly, this represents the same type of toxins that are found in the skin of so-called poison dart frogs (3,4). Endemic to New Guinea, Pitohui birds can cause irritation of mucosal membranes and eyes, as well as skin numbness when handled with bare hands (3,19). In a prominent example of convergent evolution, it is thought that Pitohui and Ifrita acquire their toxicity in the same way poison dart frogs do – by consuming batrachotoxins-containing insects (20). In turn, insects are
467
Commentary from the Editorial Board
presumed to produce batrachotoxins from phytosterols of the plants on which they feed. While the mechanisms of bird toxicity remain obscure, in a recently published issue of the journal, Menon and Dumbacher (5) explore an intriguing idea that to achieve efficient storage of batrachotoxins in their skin and feathers, Pitohui exploit the basic permeability barrier function of their epidermis. Unlike most mammals, birds in general have very thin epidermis, and their keratinocytes produce large organelles called multigranular bodies (MGB). As they mature, MGBs convert to neutral lipid droplets that maintain droplet organization and thus efficiently retain their content upon terminal differentiation of keratinocytes. Building upon the fact that the presence of toxic alkaloids in plant cells and cutaneous gland cells in poison dart frogs strongly correlates with selective osmiophilia on electron microscopy, Menon and Dumbacher (5) showed that, in comparison with non-poisonous avian species, MGBs in Pitohui epidermis are highly osmiophilic. This osmiophilia, and likely alkaloid accumulation, is selective to MGBs, suggesting that Pitohui have an active mechanism for batrachotoxins sequestration in their epidermal keratinocytes. It remains unclear how batrachotoxins incorporate into feather, which in Pitohui are just as toxic as the skin. Curiously, the oily
secretion from the uropygial gland, which birds commonly apply onto their plumage to maintain the feather’s integrity and function, can be ruled out as a significant source of batrachotoxins. In experiments, concentrated ethanol extracts of Pitohui skin and feathers, but not of the uropygial gland, have caused convulsions and quick death upon subcutaneous injection into mice (3). Taken together, the recent work by Menon and Dumbacher (5) and Kingdon and Agwanda (15) underscores the fact that skin and its various appendages in both birds and mammals can become efficient and often deadly defence tools. Moreover, it highlights that poisonousness is a common convergent evolutionary strategy that has become embedded into the complexity of vertebrate skin phenotypes.
Acknowledgements M.V.P. is supported by a Edward Mallinckrodt Jr. Foundation Research Grant and a Dermatology Foundation Research Grant. M.V.P. conceived and wrote the commentary. A.A.A. provided critical conceptual advice and assisted with writing. The authors are thankful to Dr. Fritz Vollrath and Dr. Olga Chernova for graciously permitting to reproduce their images.
Conflict of Interest The authors have declared no conflict of interest.
References 1 Ligabue-Braun R, Verli H, Carlini C R. Toxicon 2012: 59: 680–695. 2 Dufton M J. Pharmacol Ther 1992: 53: 199–215. 3 Dumbacher J P, Beehler B M, Spande T F et al. Science 1992: 258: 799–801. 4 Dumbacher J P, Spande T F, Daly J W. Proc Natl Acad Sci USA 2000: 97: 12970–12975. 5 Menon G K, Dumbacher J P. Exp Dermatol 2014: 23: 288–290. 6 Kita M, Nakamura Y, Okumura Y et al. Proc Natl Acad Sci USA 2004: 101: 7542–7547. 7 Cuenca-Bescos G, Rofes J. Naturwissenschaften 2007: 94: 113–116.
468
8 Fox R C, Scott C S. Nature 2005: 435: 1091– 1093. 9 Krause W J. Cells, Tissues, Organs 2010: 191: 336–354. 10 Whittington C M, Papenfuss A T, Locke D P et al. Genome Biol 2010: 11: R95. 11 Whittington C M, Koh J M, Warren W C et al. J proteomics 2009: 72: 155–164. 12 Fenner P J, Williamson J A, Myers D. Med J Aust 1992: 157: 829–832. 13 Li G, Luo Z X. Nature 2006: 439: 195–200. 14 Hu Y, Wang Y, Luo Z et al. Nature 1997: 390: 137–142.
15 Kingdon J, Agwanda B, Kinnaird M et al. Proc Biol Sci 2012: 279: 675–680. 16 Stoddart D M. J Zool 1979: 189: 551–553. 17 Brodie E D. Nature 1977: 268: 627–628. 18 Chernova O F. Izv Akad Nauk Ser Biol 2003: 1: 63–73. 19 Diamond J M. Nature 1992: 360: 19–20. 20 Dumbacher J P, Wako A, Derrickson S R et al. Proc Natl Acad Sci USA 2004: 101: 15857–15860.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2014, 23, 466–468
