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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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Age-dependent phenotypic changes in the replacement mice. (A) Three 8-mo-old K16 replacement littermates. The genotypes are from left to right: K16−/−, K14+/+ (wild-type), K16+/+, K14−/−, and K16+/−, K14−/−. Alopecia in these mice can begin at ∼4–5 weeks of age and usually proceeds in a head-to-tail direction. The mouse on the right has extensive epidermal ulcers. These ulcers usually occur in areas of hair loss and frequent physical contact. While ∼80% of these mice exhibit alopecia, approximately one in three develop lesions. (B) Two 7-mo-old K16-C14 replacement littermates. The genotypes of both mice are K16-C14 +/−, K14−/−. Alopecia occurs at a much lower frequency (∼33%) in these mice and lesion formation has not been noted.
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Figure 7: Age-dependent phenotypic changes in the replacement mice. (A) Three 8-mo-old K16 replacement littermates. The genotypes are from left to right: K16−/−, K14+/+ (wild-type), K16+/+, K14−/−, and K16+/−, K14−/−. Alopecia in these mice can begin at ∼4–5 weeks of age and usually proceeds in a head-to-tail direction. The mouse on the right has extensive epidermal ulcers. These ulcers usually occur in areas of hair loss and frequent physical contact. While ∼80% of these mice exhibit alopecia, approximately one in three develop lesions. (B) Two 7-mo-old K16-C14 replacement littermates. The genotypes of both mice are K16-C14 +/−, K14−/−. Alopecia occurs at a much lower frequency (∼33%) in these mice and lesion formation has not been noted.

Mentions: Beginning as early as 4–5 wk after birth, the K16 replacement mice begin to lose hair (Fig. 7 A, middle mouse). This alopecia generally initiates at the crown of the head and proceeds in a head-to-tail fashion. The loss occurs primarily on the dorsal surface but also occurs to a lesser extent on the ventral surface. Once lost, the hair does not regrow. While ∼80% of the K16 replacement mice exhibit alopecia, about one in three develop severe skin lesions (Fig. 7 A, right mouse) characterized by epidermal ulceration and scar contraction. These lesions are more prevalent in areas of hair loss and frequent physical contact (limbs, paws, eyes, nose, and mouth areas). Interestingly, the amount of K16 transgene expressed in skin does not change as a function of time. In fact, K16 transgene levels from hairless or lesional skin from the 8-mo-old mice were equivalent to the levels observed in 7-d-old skin (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)

Age-dependent phenotypic changes in the replacement mice. (A) Three 8-mo-old K16 replacement littermates. The genotypes are from left to right: K16−/−, K14+/+ (wild-type), K16+/+, K14−/−, and K16+/−, K14−/−. Alopecia in these mice can begin at ∼4–5 weeks of age and usually proceeds in a head-to-tail direction. The mouse on the right has extensive epidermal ulcers. These ulcers usually occur in areas of hair loss and frequent physical contact. While ∼80% of these mice exhibit alopecia, approximately one in three develop lesions. (B) Two 7-mo-old K16-C14 replacement littermates. The genotypes of both mice are K16-C14 +/−, K14−/−. Alopecia occurs at a much lower frequency (∼33%) in these mice and lesion formation has not been noted.
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Related In: Results  -  Collection

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Figure 7: Age-dependent phenotypic changes in the replacement mice. (A) Three 8-mo-old K16 replacement littermates. The genotypes are from left to right: K16−/−, K14+/+ (wild-type), K16+/+, K14−/−, and K16+/−, K14−/−. Alopecia in these mice can begin at ∼4–5 weeks of age and usually proceeds in a head-to-tail direction. The mouse on the right has extensive epidermal ulcers. These ulcers usually occur in areas of hair loss and frequent physical contact. While ∼80% of these mice exhibit alopecia, approximately one in three develop lesions. (B) Two 7-mo-old K16-C14 replacement littermates. The genotypes of both mice are K16-C14 +/−, K14−/−. Alopecia occurs at a much lower frequency (∼33%) in these mice and lesion formation has not been noted.
Mentions: Beginning as early as 4–5 wk after birth, the K16 replacement mice begin to lose hair (Fig. 7 A, middle mouse). This alopecia generally initiates at the crown of the head and proceeds in a head-to-tail fashion. The loss occurs primarily on the dorsal surface but also occurs to a lesser extent on the ventral surface. Once lost, the hair does not regrow. While ∼80% of the K16 replacement mice exhibit alopecia, about one in three develop severe skin lesions (Fig. 7 A, right mouse) characterized by epidermal ulceration and scar contraction. These lesions are more prevalent in areas of hair loss and frequent physical contact (limbs, paws, eyes, nose, and mouth areas). Interestingly, the amount of K16 transgene expressed in skin does not change as a function of time. In fact, K16 transgene levels from hairless or lesional skin from the 8-mo-old mice were equivalent to the levels observed in 7-d-old skin (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