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Ichthyosis Models

  • Howard MaibachEmail author
Living reference work entry

Abstract

Ichthyosis vulgaris is a heterogeneous autosomal skin disease characterized by dry, scaly skin, mild hyperkeratosis, and a decreased or absent granular layer that either lacks or contains morphologically abnormal, keratohyalin granula (Anton-Lamprecht and Hofbauer 1972). Both the skin of ichthyosis vulgaris patients and keratinocytes cultured from affected individuals exhibit reduced or absent profilaggrin mRNA and protein levels (Sybert et al. 1985). The symptoms and the genetics of the ichthyotic (ic/ic) mouse were described by Spearman (1960), Green et al. (1974), Jensen and Esterly (1977), and Holbrook (1989). Presland et al. (2000) demonstrated loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice and proposed this as an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris.

Keywords

Hairless Mouse Topical Retinoid Comparative Potency Single Gene Model Scaly Skin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Ichthyosis Vulgaris Models

Experimentally Induced Ichthyosis in Mice

Purpose and Rationale

Ichthyosis vulgaris is a heterogeneous autosomal skin disease characterized by dry, scaly skin, mild hyperkeratosis, and a decreased or absent granular layer that either lacks or contains morphologically abnormal, keratohyalin granula (Anton-Lamprecht and Hofbauer 1972). Both the skin of ichthyosis vulgaris patients and keratinocytes cultured from affected individuals exhibit reduced or absent profilaggrin mRNA and protein levels (Sybert et al. 1985). The symptoms and the genetics of the ichthyotic (ic/ic) mouse were described by Spearman (1960), Green et al. (1974), Jensen and Esterly (1977), and Holbrook (1989). Presland et al. (2000) demonstrated loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice and proposed this as an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris.

Elias et al. (1983) and Chung et al. (1984) induced ichthyosis in the hairless mouse by treatment with diazacholesterol and used this as an assay for comparative potency of topical retinoids.

Procedure

Male hairless mice, 2–3 months old, are fed either a normal laboratory diet supplemented with 60 mg/kg/day of 20,25-diazacholesterol or normal laboratory diet. Diazacholesterol blocks the conversion of Δ24-reduction of desmosterol to cholesterol (Anderson and Martt 1965), and as a result, desmosterol accumulates in the stratum corneum as lipids rather than as cholesterol. Ichthyotic changes generally become apparent after 8–12 weeks and are most pronounced over the back and tail. With the exception of some reduction in body weight in comparison with controls, the animals appear healthy. Since the tail manifests the most exaggerated scaling, this site is used for topical drug applications. As the animals become ichthyotic, the daily dose of diazacholesterol can be lowered to 30 mg/kg and maintained at that level.

The test substances (retinoids) are first solubilized in a small volume of dimethyl sulfoxide and then dissolved in Cremophor EL. A volume of ∼100 μl of each test substance is applied once daily to the circumscribed areas of the tail. Treatment groups consist of three animals each, and each animal serves as its own control. The drop is first placed on an investigator’s gloved index finger and is then spread evenly around a designated band of the tail. Each animal is treated with two concentrations of the test drug. The most proximal and most distal portions of the tail are left untreated as control regions. Applications are continued for 2 weeks. At three- or four-day intervals, and at the termination of the experiment, the clinical response is graded from 0 to 4+, with 0 indicating no response and 4+ indicating removal of all visible scale, leaving a glistening surface.

Prior to biopsy, the skin surface is coated with a thin film of flexible collodion to prevent fragmentation during frozen sectioning. Perpendicular sections of biopsy samples are stained with aqueous 8-anilino-2-naphthalene sulfonic acid, which on fluorescence microscopy depict selectively stratum corneum hydrophobic membrane domains.

Evaluation

Both the control and drug-treated sections are measured in a double-blind manner. The mean and SE from a minimum of five separate regions are tabulated. Significant differences are determined by Student’s t-test.

Modifications of the Method

Harlequin Ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis was described by Sundberg et al. (1997).

Shultz et al. (2003) described mutations at the mouse ichthyosis locus within the lamin B-receptor gene as a single gene model for human Pelger-Huet anomaly.

Knox and Lister-Rosenoer (1998) described an infantile ichthyosis in rats and proposed this as a new model of hyperkeratotic skin disease.

References and Further Reading

  • Anderson PC, Martt JM (1965) Myotonia and keratoderma induced by 20,25-diazacholesterol. Arch Dermatol 92:181–187

  • Anton-Lamprecht I, Hofbauer M (1972) Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Humangenetik 15:261–264

  • Chung J-C, Law MYL, Elliott ST, Elias PM (1984) Diazacholesterol-induced ichthyosis in the hairless mouse. Assay for comparative potency of topical retinoids. Arch Dermatol 120:342–347

  • Elias PM, Lampe MA, Chung JC, Williams ML (1983) Diazacholesterol-induced ichthyosis in the hairless mouse. I. Morphologic, histochemical, and lipid biochemical characterization of a new animal model. Lab Invest 48:565–577

  • Green MC, Alpert BN, Mayer TC (1974) The site of action of the ichthyosis locus (ic) in the mouse as determined by dermal-epidermal recombinations. J Embryol Exp Morphol 32:715–724

  • Holbrook KA (1989) Ichthyosis, inherited, skin mouse (ic/ic). In: Jones TC, Mohr U, Hunt RD (eds) Integument and mammary glands, Monographs on pathology of laboratory animals. Springer, Heidelberg, pp 223–229

  • Jensen JE, Esterly NB (1977) The ichthyosis mouse: histologic, histochemical, ultrastructural, and autoradiographic studies of interfollicular epidermis. J Invest Dermatol 68:23–31

  • Knox WE, Lister-Rosenoer LM (1998) Infantile ichthyosis in rats: a new model of hyperkeratotic skin disease. J Hered 69:391–394

  • Nirunsuksiri W, Presland RB, Brumbaugh SG, Dale BA, Fleckman P (1995) Decreased profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired post-transcriptional control. J Biol Chem 270:871–876

  • Presland RB, Boggess D, Lewis SP, Hull C, Fleckman P, Sundberg JP (2000) Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol 115:1072–1081

  • Shultz LD, Lyons BL, Burzenski LM, Gott B, Samuels R, Schweitzer PA, Dreger C, Herrmann H, Kalscheuer V, Olins AL, Olins DE, Sperling K, Hoffmann K (2003) Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly. Hum Mol Genet 12:61–69

  • Spearman RJ (1960) The skin abnormality of “ichthyosis”, a mutant of the house mouse. J Embryol Exp Morphol 8:387–395

  • Sundberg JP, Boggess D, Hogan ME, Sundberg BA, Rourk MH, Harris B, Johnson K, Dunstan RW, Davisson MT (1997) Harlequin ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis. Am J Pathol 151:293–310

  • Sybert VP, Dale BA, Holbrook KA (1985) Ichthyosis vulgaris: identification of a defect in syntheses of filaggrin correlated with an absence of keratohyline granules. J Invest Dermatol 84:191–194

References and Further Reading

  1. Anderson PC, Martt JM (1965) Myotonia and keratoderma induced by 20,25-diazacholesterol. Arch Dermatol 92:181–187CrossRefGoogle Scholar
  2. Anton-Lamprecht I, Hofbauer M (1972) Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Humangenetik 15:261–264PubMedGoogle Scholar
  3. Chung J-C, Law MYL, Elliott ST, Elias PM (1984) Diazacholesterol-induced ichthyosis in the hairless mouse. Assay for comparative potency of topical retinoids. Arch Dermatol 120:342–347CrossRefPubMedGoogle Scholar
  4. Elias PM, Lampe MA, Chung JC, Williams ML (1983) Diazacholesterol-induced ichthyosis in the hairless mouse. I. Morphologic, histochemical, and lipid biochemical characterization of a new animal model. Lab Invest 48:565–577PubMedGoogle Scholar
  5. Green MC, Alpert BN, Mayer TC (1974) The site of action of the ichthyosis locus (ic) in the mouse as determined by dermal-epidermal recombinations. J Embryol Exp Morphol 32:715–724PubMedGoogle Scholar
  6. Holbrook KA (1989) Ichthyosis, inherited, skin mouse (ic/ic). In: Jones TC, Mohr U, Hunt RD (eds) Integument and mammary glands, Monographs on pathology of laboratory animals. Springer, Heidelberg, pp 223–229CrossRefGoogle Scholar
  7. Jensen JE, Esterly NB (1977) The ichthyosis mouse: histologic, histochemical, ultrastructural, and autoradiographic studies of interfollicular epidermis. J Invest Dermatol 68:23–31CrossRefPubMedGoogle Scholar
  8. Knox WE, Lister-Rosenoer LM (1998) Infantile ichthyosis in rats: a new model of hyperkeratotic skin disease. J Hered 69:391–394Google Scholar
  9. Nirunsuksiri W, Presland RB, Brumbaugh SG, Dale BA, Fleckman P (1995) Decreased profilaggrin expression in ichthyosis vulgaris is a result of selectively impaired post-transcriptional control. J Biol Chem 270:871–876CrossRefPubMedGoogle Scholar
  10. Presland RB, Boggess D, Lewis SP, Hull C, Fleckman P, Sundberg JP (2000) Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol 115:1072–1081CrossRefPubMedGoogle Scholar
  11. Shultz LD, Lyons BL, Burzenski LM, Gott B, Samuels R, Schweitzer PA, Dreger C, Herrmann H, Kalscheuer V, Olins AL, Olins DE, Sperling K, Hoffmann K (2003) Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly. Hum Mol Genet 12:61–69CrossRefPubMedGoogle Scholar
  12. Spearman RJ (1960) The skin abnormality of “ichthyosis”, a mutant of the house mouse. J Embryol Exp Morphol 8:387–395Google Scholar
  13. Sundberg JP, Boggess D, Hogan ME, Sundberg BA, Rourk MH, Harris B, Johnson K, Dunstan RW, Davisson MT (1997) Harlequin ichthyosis (ichq): a juvenile lethal mouse mutation with ichthyosiform dermatitis. Am J Pathol 151:293–310PubMedCentralPubMedGoogle Scholar
  14. Sybert VP, Dale BA, Holbrook KA (1985) Ichthyosis vulgaris: identification of a defect in syntheses of filaggrin correlated with an absence of keratohyline granules. J Invest Dermatol 84:191–194CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of DermatologyUC San FranciscoSan FranciscoUSA

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