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Discovery of a novel murine keratin 6 (K6) isoform explains the absence of hair and nail defects in mice deficient for K6a and K6b.

Wojcik SM, Longley MA, Roop DR - J. Cell Biol. (2001)

Bottom Line: We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles.We therefore termed this gene MK6 hair follicle (MK6hf).The presence of MK6hf in the MK6a/b-/- follicles and nails offers an explanation for the absence of hair and nail defects in MK6a/b-/- animals.

View Article: PubMed Central - PubMed

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

ABSTRACT
The murine genome is known to have two keratin 6 (K6) genes, mouse K6 (MK6)a and MK6b. These genes display a complex expression pattern with constitutive expression in the epithelia of oral mucosa, hair follicles, and nail beds. We generated mice deficient for both genes through embryonic stem cell technology. The majority of MK6a/b-/- mice die of starvation within the first two weeks of life. This is due to a localized disintegration of the dorsal tongue epithelium, which results in the build up of a plaque of cell debris that severely impairs feeding. However, approximately 25% of MK6a/b-/- mice survive to adulthood. Remarkably, the surviving MK6a/b-/- mice have normal hair and nails. To our surprise, we discovered MK6 staining both in the hair follicle and the nail bed of MK6a/b-/- mice, indicating the presence of a third MK6 gene. We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles. We therefore termed this gene MK6 hair follicle (MK6hf). The presence of MK6hf in the MK6a/b-/- follicles and nails offers an explanation for the absence of hair and nail defects in MK6a/b-/- animals.

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Related in: MedlinePlus

Oral lesions in MK6a/b−/− mice occur in the back of the oral cavity where MK6b expression in the tongue is highest in wild-type animals. (a) MK6a/b−/− pup (top) at 8 d showing signs of starvation. A wild-type littermate is shown for comparison. (b) Lower jaw of 8-d-old MK6a/b+/− pup. The tongue appears smooth. (c) Lower jaw of 8-d-old MK6a/b−/− pup. Note the white plaque in the back and center of the tongue (arrow). (d) MK6a/b+/+ tongue and palate in the back of the oral cavity of 10-d-old pup. (e) MK6a/b−/− tongue and palate in the back of the oral cavity of 10-d-old pup, showing plaque formation on the tongue and palate epithelium. Note that the plaque on the tongue (⋆) fills almost the entire oral cavity. (f) MK6a/b+/+ tongue epithelium at high magnification showing the appearance of the papillae from the back of the tongue. (g) MK6a/b−/− tongue epithelium at high magnification showing that the plaque is composed of cell remnants that remain attached to each other. Note that the superficial cells of the papillae appear to be losing their cytoplasmic content and nuclei. (h–k) Images stained with MK6b/hf (red) and MK16 (green) antibodies; areas with overlapping staining appear yellow. (h) MK6a/b+/+, note that in the middle of the tongue MK6b is restricted to the uppermost cells of the papillae (arrow). (i) The middle of the MK6a/b−/− tongue epithelium appears intact in spite of the absence of MK6. (j) MK6a/b+/+, note that in the back of the tongue MK6b is expressed throughout the papillae. (k) MK6a/b−/− lesion in the back of the tongue epithelium, which corresponds to the site where MK6b expression is most widespread in wild-type tongue. Bars, 100 μm.
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fig2: Oral lesions in MK6a/b−/− mice occur in the back of the oral cavity where MK6b expression in the tongue is highest in wild-type animals. (a) MK6a/b−/− pup (top) at 8 d showing signs of starvation. A wild-type littermate is shown for comparison. (b) Lower jaw of 8-d-old MK6a/b+/− pup. The tongue appears smooth. (c) Lower jaw of 8-d-old MK6a/b−/− pup. Note the white plaque in the back and center of the tongue (arrow). (d) MK6a/b+/+ tongue and palate in the back of the oral cavity of 10-d-old pup. (e) MK6a/b−/− tongue and palate in the back of the oral cavity of 10-d-old pup, showing plaque formation on the tongue and palate epithelium. Note that the plaque on the tongue (⋆) fills almost the entire oral cavity. (f) MK6a/b+/+ tongue epithelium at high magnification showing the appearance of the papillae from the back of the tongue. (g) MK6a/b−/− tongue epithelium at high magnification showing that the plaque is composed of cell remnants that remain attached to each other. Note that the superficial cells of the papillae appear to be losing their cytoplasmic content and nuclei. (h–k) Images stained with MK6b/hf (red) and MK16 (green) antibodies; areas with overlapping staining appear yellow. (h) MK6a/b+/+, note that in the middle of the tongue MK6b is restricted to the uppermost cells of the papillae (arrow). (i) The middle of the MK6a/b−/− tongue epithelium appears intact in spite of the absence of MK6. (j) MK6a/b+/+, note that in the back of the tongue MK6b is expressed throughout the papillae. (k) MK6a/b−/− lesion in the back of the tongue epithelium, which corresponds to the site where MK6b expression is most widespread in wild-type tongue. Bars, 100 μm.

Mentions: Litters from the first MK6a/b+/− crosses were genotyped shortly after birth (Fig. 1 c), and MK6a/b+/+, MK6a/b+/−, and MK6a/b−/− animals were found at the expected Mendelian frequencies. However, the majority (∼75%) of MK6a/b−/− mice subsequently failed to thrive, which became apparent at different times in different animals. The majority of MK6a/b−/− pups began to lag behind in their growth when compared with the MK6a/b+/+ and MK6a/b+/− littermates between the ages of 3 and 7 d after birth. Such pups progressively became more emaciated over the course of 3–5 d and ultimately died of apparent starvation, usually before they reached 2 wk of age. Shown are a MK6a/b−/− pup and a MK6a/b+/+ pup at 8 d of age (Fig. 2 a). However, some MK6a/b−/− animals were outwardly indistinguishable from their MK6a/b+/+ and MK6a/b+/− littermates and survived to adulthood. Out of 109 pups that were genotyped after weaning, 70 were heterozygotes, 30 wild type, and 9 were surviving knockouts. Since we had previously found a normal Mendelian distribution of MK6a/b+/−, MK6a/b+/+, and MK6a/b−/− genotypes in litters screened immediately after birth, we estimated, based on the numbers shown above, the survival rate of MK6a/b−/− animals to be 27%. The surviving MK6a/b−/− animals reached normal adult size and were fertile. Matings of MK6a/b−/− animals produced litters with survival rates that varied between litters and ranged from 50–100%. This strongly suggests a genetic, rather than environmental reason for the survival of some of the MK6a/b−/− animals.


Discovery of a novel murine keratin 6 (K6) isoform explains the absence of hair and nail defects in mice deficient for K6a and K6b.

Wojcik SM, Longley MA, Roop DR - J. Cell Biol. (2001)

Oral lesions in MK6a/b−/− mice occur in the back of the oral cavity where MK6b expression in the tongue is highest in wild-type animals. (a) MK6a/b−/− pup (top) at 8 d showing signs of starvation. A wild-type littermate is shown for comparison. (b) Lower jaw of 8-d-old MK6a/b+/− pup. The tongue appears smooth. (c) Lower jaw of 8-d-old MK6a/b−/− pup. Note the white plaque in the back and center of the tongue (arrow). (d) MK6a/b+/+ tongue and palate in the back of the oral cavity of 10-d-old pup. (e) MK6a/b−/− tongue and palate in the back of the oral cavity of 10-d-old pup, showing plaque formation on the tongue and palate epithelium. Note that the plaque on the tongue (⋆) fills almost the entire oral cavity. (f) MK6a/b+/+ tongue epithelium at high magnification showing the appearance of the papillae from the back of the tongue. (g) MK6a/b−/− tongue epithelium at high magnification showing that the plaque is composed of cell remnants that remain attached to each other. Note that the superficial cells of the papillae appear to be losing their cytoplasmic content and nuclei. (h–k) Images stained with MK6b/hf (red) and MK16 (green) antibodies; areas with overlapping staining appear yellow. (h) MK6a/b+/+, note that in the middle of the tongue MK6b is restricted to the uppermost cells of the papillae (arrow). (i) The middle of the MK6a/b−/− tongue epithelium appears intact in spite of the absence of MK6. (j) MK6a/b+/+, note that in the back of the tongue MK6b is expressed throughout the papillae. (k) MK6a/b−/− lesion in the back of the tongue epithelium, which corresponds to the site where MK6b expression is most widespread in wild-type tongue. Bars, 100 μm.
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fig2: Oral lesions in MK6a/b−/− mice occur in the back of the oral cavity where MK6b expression in the tongue is highest in wild-type animals. (a) MK6a/b−/− pup (top) at 8 d showing signs of starvation. A wild-type littermate is shown for comparison. (b) Lower jaw of 8-d-old MK6a/b+/− pup. The tongue appears smooth. (c) Lower jaw of 8-d-old MK6a/b−/− pup. Note the white plaque in the back and center of the tongue (arrow). (d) MK6a/b+/+ tongue and palate in the back of the oral cavity of 10-d-old pup. (e) MK6a/b−/− tongue and palate in the back of the oral cavity of 10-d-old pup, showing plaque formation on the tongue and palate epithelium. Note that the plaque on the tongue (⋆) fills almost the entire oral cavity. (f) MK6a/b+/+ tongue epithelium at high magnification showing the appearance of the papillae from the back of the tongue. (g) MK6a/b−/− tongue epithelium at high magnification showing that the plaque is composed of cell remnants that remain attached to each other. Note that the superficial cells of the papillae appear to be losing their cytoplasmic content and nuclei. (h–k) Images stained with MK6b/hf (red) and MK16 (green) antibodies; areas with overlapping staining appear yellow. (h) MK6a/b+/+, note that in the middle of the tongue MK6b is restricted to the uppermost cells of the papillae (arrow). (i) The middle of the MK6a/b−/− tongue epithelium appears intact in spite of the absence of MK6. (j) MK6a/b+/+, note that in the back of the tongue MK6b is expressed throughout the papillae. (k) MK6a/b−/− lesion in the back of the tongue epithelium, which corresponds to the site where MK6b expression is most widespread in wild-type tongue. Bars, 100 μm.
Mentions: Litters from the first MK6a/b+/− crosses were genotyped shortly after birth (Fig. 1 c), and MK6a/b+/+, MK6a/b+/−, and MK6a/b−/− animals were found at the expected Mendelian frequencies. However, the majority (∼75%) of MK6a/b−/− mice subsequently failed to thrive, which became apparent at different times in different animals. The majority of MK6a/b−/− pups began to lag behind in their growth when compared with the MK6a/b+/+ and MK6a/b+/− littermates between the ages of 3 and 7 d after birth. Such pups progressively became more emaciated over the course of 3–5 d and ultimately died of apparent starvation, usually before they reached 2 wk of age. Shown are a MK6a/b−/− pup and a MK6a/b+/+ pup at 8 d of age (Fig. 2 a). However, some MK6a/b−/− animals were outwardly indistinguishable from their MK6a/b+/+ and MK6a/b+/− littermates and survived to adulthood. Out of 109 pups that were genotyped after weaning, 70 were heterozygotes, 30 wild type, and 9 were surviving knockouts. Since we had previously found a normal Mendelian distribution of MK6a/b+/−, MK6a/b+/+, and MK6a/b−/− genotypes in litters screened immediately after birth, we estimated, based on the numbers shown above, the survival rate of MK6a/b−/− animals to be 27%. The surviving MK6a/b−/− animals reached normal adult size and were fertile. Matings of MK6a/b−/− animals produced litters with survival rates that varied between litters and ranged from 50–100%. This strongly suggests a genetic, rather than environmental reason for the survival of some of the MK6a/b−/− animals.

Bottom Line: We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles.We therefore termed this gene MK6 hair follicle (MK6hf).The presence of MK6hf in the MK6a/b-/- follicles and nails offers an explanation for the absence of hair and nail defects in MK6a/b-/- animals.

View Article: PubMed Central - PubMed

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

ABSTRACT
The murine genome is known to have two keratin 6 (K6) genes, mouse K6 (MK6)a and MK6b. These genes display a complex expression pattern with constitutive expression in the epithelia of oral mucosa, hair follicles, and nail beds. We generated mice deficient for both genes through embryonic stem cell technology. The majority of MK6a/b-/- mice die of starvation within the first two weeks of life. This is due to a localized disintegration of the dorsal tongue epithelium, which results in the build up of a plaque of cell debris that severely impairs feeding. However, approximately 25% of MK6a/b-/- mice survive to adulthood. Remarkably, the surviving MK6a/b-/- mice have normal hair and nails. To our surprise, we discovered MK6 staining both in the hair follicle and the nail bed of MK6a/b-/- mice, indicating the presence of a third MK6 gene. We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles. We therefore termed this gene MK6 hair follicle (MK6hf). The presence of MK6hf in the MK6a/b-/- follicles and nails offers an explanation for the absence of hair and nail defects in MK6a/b-/- animals.

Show MeSH
Related in: MedlinePlus