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Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders.

Arin MJ, Longley MA, Wang XJ, Roop DR - J. Cell Biol. (2001)

Bottom Line: This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase.Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes.This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

ABSTRACT
Stem cells are crucial for the formation and maintenance of tissues and organs. The role of stem cells in the pathogenesis of mosaic skin disorders remains unclear. To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase. Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

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Chimeric mice derived from +/mutloxP ES cells. Thick hyperkeratoses on the paws at 5 wk (A) and 3 mo of age (B). (C) Normal paw.
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Figure 3: Chimeric mice derived from +/mutloxP ES cells. Thick hyperkeratoses on the paws at 5 wk (A) and 3 mo of age (B). (C) Normal paw.

Mentions: Persistent “islands” of phenotypic skin were also observed in chimeric mice derived from +/mutloxP ES cell clones, where the neo cassette had been excised in vitro before injection into wild-type blastocysts. These mice exhibited focal keratotic lesions on the paws at birth that developed into thick, brownish hyperkeratoses (Fig. 3A and Fig. B). The focal lesions in both the inducible model system and the chimeras are equivalent to the linear, asymmetric hyperkeratotic areas in humans in the mosaic form of EHK, which is characterized by alternating stripes of affected and unaffected skin that follow the lines of Blaschko (Happle 1987). It has been shown that the mosaic form is caused by postzygotic K10 mutations that occur during embryogenesis (Paller et al. 1994). Our analysis of the inducible mouse model clearly suggests that in EHK, mutant epidermal stem cells exist side by side with wild-type stem cells. As the mutant K10 allele is not expressed in the basal layer, there is no selection against mutant EHK epidermal stem cells. In contrast, a selection process takes place against defective epidermal stem cells in a mouse model for EBS, when the mutant allele is focally activated in the basal layer (Cao et al. 2001). This could explain why mosaic forms exist for EHK, but not for EBS.


Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders.

Arin MJ, Longley MA, Wang XJ, Roop DR - J. Cell Biol. (2001)

Chimeric mice derived from +/mutloxP ES cells. Thick hyperkeratoses on the paws at 5 wk (A) and 3 mo of age (B). (C) Normal paw.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195990&req=5

Figure 3: Chimeric mice derived from +/mutloxP ES cells. Thick hyperkeratoses on the paws at 5 wk (A) and 3 mo of age (B). (C) Normal paw.
Mentions: Persistent “islands” of phenotypic skin were also observed in chimeric mice derived from +/mutloxP ES cell clones, where the neo cassette had been excised in vitro before injection into wild-type blastocysts. These mice exhibited focal keratotic lesions on the paws at birth that developed into thick, brownish hyperkeratoses (Fig. 3A and Fig. B). The focal lesions in both the inducible model system and the chimeras are equivalent to the linear, asymmetric hyperkeratotic areas in humans in the mosaic form of EHK, which is characterized by alternating stripes of affected and unaffected skin that follow the lines of Blaschko (Happle 1987). It has been shown that the mosaic form is caused by postzygotic K10 mutations that occur during embryogenesis (Paller et al. 1994). Our analysis of the inducible mouse model clearly suggests that in EHK, mutant epidermal stem cells exist side by side with wild-type stem cells. As the mutant K10 allele is not expressed in the basal layer, there is no selection against mutant EHK epidermal stem cells. In contrast, a selection process takes place against defective epidermal stem cells in a mouse model for EBS, when the mutant allele is focally activated in the basal layer (Cao et al. 2001). This could explain why mosaic forms exist for EHK, but not for EBS.

Bottom Line: This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase.Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes.This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.

ABSTRACT
Stem cells are crucial for the formation and maintenance of tissues and organs. The role of stem cells in the pathogenesis of mosaic skin disorders remains unclear. To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a somatic K10 mutation in epidermal stem cells in a spatially and temporally controlled manner using an inducible Cre recombinase. Our results indicate that lack of selective pressure against certain mutations in epidermal stem cells leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant genodermatoses.

Show MeSH
Related in: MedlinePlus