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The functional diversity of epidermal keratins revealed by the partial rescue of the keratin 14 phenotype by keratin 16.

Paladini RD, Coulombe PA - J. Cell Biol. (1999)

Bottom Line: Degenstein, E.Fuchs. 1995.Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Chemistry and Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

ABSTRACT
The type I epidermal keratins K14 and K16 are remarkably similar at the primary sequence level. While a structural function has been clearly defined for K14, we have proposed that a function of K16 may be to play a role in the process of keratinocyte activation that occurs after acute injury to stratified epithelia. To compare directly the functions of the two keratins we have targeted the expression of the human K16 cDNA to the progenitor basal layer of the epidermis of K14 mice. Mice for K14 blister extensively and die approximately 2 d after birth (Lloyd, C., Q.C. Yu, J. Cheng, K. Turksen, L. Degenstein, E. Hutton, and E. Fuchs. 1995. J. Cell Biol. 129:1329-1344). The skin of mice expressing K16 in the absence of K14 developed normally without evidence of blistering. However, as the mice aged they featured extensive alopecia, chronic epidermal ulcers in areas of frequent physical contact, and alterations in other stratified epithelia. Mice expressing a control K16-C14 cDNA also rescue the blistering phenotype of the K14 mice with only a small percentage exhibiting minor alopecia. While K16 is capable of rescuing the blistering, phenotypic complementation in the resulting skin is incomplete due to the multiple age dependent anomalies. Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

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Light microscopy of various stratified epithelia from K16-C14 control and phenotypic K16 replacement mice. 5-μm paraffin sections from 8-mo-old K16-C14 and K16 replacement mice were counterstained with hematoxylin and eosin (H & E). (A–D) Dorsal skin sections from a K16 replacement mouse. Hairy skin (A) has a thin epidermis and telogen staged hair follicles. Skin from a hairless region (B) features a thickened epidermis and an increase in the number of sebaceous glands. Some of the anagen staged hair follicles are improperly oriented (large arrowhead) and are missing their hair shafts (large asterisk). Skin from lesional areas (C and D) has a hyperplastic epidermis, an expansion of the outer root sheath of the hair follicles, and a large dermal infiltrate suggestive of an inflammatory response. There are also large cysts derived from pilosebaceous units (large asterisk). There are signs of migration of the epidermis into ulcerated areas of the skin (arrows in D). Dorsal skin sections from a K16-C14 replacement mouse. Hairy skin (E) was morphologically similar to K16 replacement hairy skin (A). Hairless K16-C14 skin (F) also exhibited many of the same aberrations observed in the K16 replacement hairless sample (B). There were also groups of melanocytes in the dermis not associated with hair follicles (arrows). This was also observed in K16 hairless and lesional skin (data not shown). Forestomach epithelium from a K16-C14 control (G) and a K16 replacement mouse (H). In the K16 replacement sample (H) there is extensive basal layer cytolysis along the length of the forestomach (arrows), while the K16-C14 sample features a normal morphology (G). Cornea from a K16-C14 control (I) and a K16 replacement mouse (J). The normal morphology and differentiation of the cornea is completely disrupted when compared with control (I) and there is a large dermal infiltrate in the underlying connective tissue (J). hf, hair follicle; sg, sebaceous gland. Arrowheads, indicate the junction between the stratified epithelium and the underlying connective tissue (A–D, the dermal-epidermal junction). Bar, 100 μm.
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Figure 8: Light microscopy of various stratified epithelia from K16-C14 control and phenotypic K16 replacement mice. 5-μm paraffin sections from 8-mo-old K16-C14 and K16 replacement mice were counterstained with hematoxylin and eosin (H & E). (A–D) Dorsal skin sections from a K16 replacement mouse. Hairy skin (A) has a thin epidermis and telogen staged hair follicles. Skin from a hairless region (B) features a thickened epidermis and an increase in the number of sebaceous glands. Some of the anagen staged hair follicles are improperly oriented (large arrowhead) and are missing their hair shafts (large asterisk). Skin from lesional areas (C and D) has a hyperplastic epidermis, an expansion of the outer root sheath of the hair follicles, and a large dermal infiltrate suggestive of an inflammatory response. There are also large cysts derived from pilosebaceous units (large asterisk). There are signs of migration of the epidermis into ulcerated areas of the skin (arrows in D). Dorsal skin sections from a K16-C14 replacement mouse. Hairy skin (E) was morphologically similar to K16 replacement hairy skin (A). Hairless K16-C14 skin (F) also exhibited many of the same aberrations observed in the K16 replacement hairless sample (B). There were also groups of melanocytes in the dermis not associated with hair follicles (arrows). This was also observed in K16 hairless and lesional skin (data not shown). Forestomach epithelium from a K16-C14 control (G) and a K16 replacement mouse (H). In the K16 replacement sample (H) there is extensive basal layer cytolysis along the length of the forestomach (arrows), while the K16-C14 sample features a normal morphology (G). Cornea from a K16-C14 control (I) and a K16 replacement mouse (J). The normal morphology and differentiation of the cornea is completely disrupted when compared with control (I) and there is a large dermal infiltrate in the underlying connective tissue (J). hf, hair follicle; sg, sebaceous gland. Arrowheads, indicate the junction between the stratified epithelium and the underlying connective tissue (A–D, the dermal-epidermal junction). Bar, 100 μm.

Mentions: As mentioned, a subset of the K16 replacement mice exhibit hair loss and the development of skin ulcerations. To understand these further, tissue samples from 8-mo-old K16-C14 control and phenotypic K16 replacement mice were taken from skin and a variety of other stratified epithelia and examined by light microscopy. Nonphenotypic, hairy skin from a K16 replacement mouse (Fig. 8 A) was similar to wild-type and K16-C14 control skin (Fig. 8 E). The epidermis was thin and there were many hair follicles. However, the hair follicles were in the telogen stage as opposed to wild-type skin in which the follicles were in anagen (data not shown). K16 transgene expression was still restricted to the basal layer (data not shown). There was no evidence of hyperproliferation as the epidermis did not stain for K6 and K17 (data not shown).


The functional diversity of epidermal keratins revealed by the partial rescue of the keratin 14 phenotype by keratin 16.

Paladini RD, Coulombe PA - J. Cell Biol. (1999)

Light microscopy of various stratified epithelia from K16-C14 control and phenotypic K16 replacement mice. 5-μm paraffin sections from 8-mo-old K16-C14 and K16 replacement mice were counterstained with hematoxylin and eosin (H & E). (A–D) Dorsal skin sections from a K16 replacement mouse. Hairy skin (A) has a thin epidermis and telogen staged hair follicles. Skin from a hairless region (B) features a thickened epidermis and an increase in the number of sebaceous glands. Some of the anagen staged hair follicles are improperly oriented (large arrowhead) and are missing their hair shafts (large asterisk). Skin from lesional areas (C and D) has a hyperplastic epidermis, an expansion of the outer root sheath of the hair follicles, and a large dermal infiltrate suggestive of an inflammatory response. There are also large cysts derived from pilosebaceous units (large asterisk). There are signs of migration of the epidermis into ulcerated areas of the skin (arrows in D). Dorsal skin sections from a K16-C14 replacement mouse. Hairy skin (E) was morphologically similar to K16 replacement hairy skin (A). Hairless K16-C14 skin (F) also exhibited many of the same aberrations observed in the K16 replacement hairless sample (B). There were also groups of melanocytes in the dermis not associated with hair follicles (arrows). This was also observed in K16 hairless and lesional skin (data not shown). Forestomach epithelium from a K16-C14 control (G) and a K16 replacement mouse (H). In the K16 replacement sample (H) there is extensive basal layer cytolysis along the length of the forestomach (arrows), while the K16-C14 sample features a normal morphology (G). Cornea from a K16-C14 control (I) and a K16 replacement mouse (J). The normal morphology and differentiation of the cornea is completely disrupted when compared with control (I) and there is a large dermal infiltrate in the underlying connective tissue (J). hf, hair follicle; sg, sebaceous gland. Arrowheads, indicate the junction between the stratified epithelium and the underlying connective tissue (A–D, the dermal-epidermal junction). Bar, 100 μm.
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Related In: Results  -  Collection

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Figure 8: Light microscopy of various stratified epithelia from K16-C14 control and phenotypic K16 replacement mice. 5-μm paraffin sections from 8-mo-old K16-C14 and K16 replacement mice were counterstained with hematoxylin and eosin (H & E). (A–D) Dorsal skin sections from a K16 replacement mouse. Hairy skin (A) has a thin epidermis and telogen staged hair follicles. Skin from a hairless region (B) features a thickened epidermis and an increase in the number of sebaceous glands. Some of the anagen staged hair follicles are improperly oriented (large arrowhead) and are missing their hair shafts (large asterisk). Skin from lesional areas (C and D) has a hyperplastic epidermis, an expansion of the outer root sheath of the hair follicles, and a large dermal infiltrate suggestive of an inflammatory response. There are also large cysts derived from pilosebaceous units (large asterisk). There are signs of migration of the epidermis into ulcerated areas of the skin (arrows in D). Dorsal skin sections from a K16-C14 replacement mouse. Hairy skin (E) was morphologically similar to K16 replacement hairy skin (A). Hairless K16-C14 skin (F) also exhibited many of the same aberrations observed in the K16 replacement hairless sample (B). There were also groups of melanocytes in the dermis not associated with hair follicles (arrows). This was also observed in K16 hairless and lesional skin (data not shown). Forestomach epithelium from a K16-C14 control (G) and a K16 replacement mouse (H). In the K16 replacement sample (H) there is extensive basal layer cytolysis along the length of the forestomach (arrows), while the K16-C14 sample features a normal morphology (G). Cornea from a K16-C14 control (I) and a K16 replacement mouse (J). The normal morphology and differentiation of the cornea is completely disrupted when compared with control (I) and there is a large dermal infiltrate in the underlying connective tissue (J). hf, hair follicle; sg, sebaceous gland. Arrowheads, indicate the junction between the stratified epithelium and the underlying connective tissue (A–D, the dermal-epidermal junction). Bar, 100 μm.
Mentions: As mentioned, a subset of the K16 replacement mice exhibit hair loss and the development of skin ulcerations. To understand these further, tissue samples from 8-mo-old K16-C14 control and phenotypic K16 replacement mice were taken from skin and a variety of other stratified epithelia and examined by light microscopy. Nonphenotypic, hairy skin from a K16 replacement mouse (Fig. 8 A) was similar to wild-type and K16-C14 control skin (Fig. 8 E). The epidermis was thin and there were many hair follicles. However, the hair follicles were in the telogen stage as opposed to wild-type skin in which the follicles were in anagen (data not shown). K16 transgene expression was still restricted to the basal layer (data not shown). There was no evidence of hyperproliferation as the epidermis did not stain for K6 and K17 (data not shown).

Bottom Line: Degenstein, E.Fuchs. 1995.Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Chemistry and Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

ABSTRACT
The type I epidermal keratins K14 and K16 are remarkably similar at the primary sequence level. While a structural function has been clearly defined for K14, we have proposed that a function of K16 may be to play a role in the process of keratinocyte activation that occurs after acute injury to stratified epithelia. To compare directly the functions of the two keratins we have targeted the expression of the human K16 cDNA to the progenitor basal layer of the epidermis of K14 mice. Mice for K14 blister extensively and die approximately 2 d after birth (Lloyd, C., Q.C. Yu, J. Cheng, K. Turksen, L. Degenstein, E. Hutton, and E. Fuchs. 1995. J. Cell Biol. 129:1329-1344). The skin of mice expressing K16 in the absence of K14 developed normally without evidence of blistering. However, as the mice aged they featured extensive alopecia, chronic epidermal ulcers in areas of frequent physical contact, and alterations in other stratified epithelia. Mice expressing a control K16-C14 cDNA also rescue the blistering phenotype of the K14 mice with only a small percentage exhibiting minor alopecia. While K16 is capable of rescuing the blistering, phenotypic complementation in the resulting skin is incomplete due to the multiple age dependent anomalies. Despite their high sequence similarity, K16 and K14 are not functionally equivalent in the epidermis and other stratified epithelia and it is primarily the carboxy-terminal approximately 105 amino acids of K16 that define these differences.

Show MeSH
Related in: MedlinePlus