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. 2010 Jan;47(1):167-76.
doi: 10.1177/0300985809352970.

Molecular basis for hair loss in mice carrying a novel nonsense mutation (Hrrh-R ) in the hairless gene (Hr)

Y Liu  1 , J P Sundberg, S Das, D Carpenter, K T Cain, E J Michaud, B H Voy
Affiliations

Molecular basis for hair loss in mice carrying a novel nonsense mutation (Hrrh-R ) in the hairless gene (Hr)

Y Liu et al. Vet Pathol. 2010 Jan.

Abstract

Animal models carrying mutations in the hairless (Hr) gene provide a rich resource for study of hair follicle biology. A spontaneous mouse mutant with a phenotype strikingly similar to rhino mutants of Hr arose spontaneously in the mouse facility at Oak Ridge National Laboratory. Sequence analysis of Hr in these mutants uncovered a nonsense mutation in exon 12, designated as Hr(rh-R) (rhino, Oak Ridge). The mutation led to significant reduction in Hr mRNA levels, predicted to be due to nonsense-mediated decay. Histological analysis indicated dilated hair follicle infundibula at 14 days of age that rapidly became filled with cornified material. Microarray analyses revealed that expression levels of many genes involved in keratinocyte differentiation, epidermal regeneration, and wound healing were significantly upregulated before morphological detection of the phenotype, suggesting their role in onset of the Hr(rh-R) phenotype. Identification of this new Hr allele and the underlying molecular alterations allows further understanding of the role of Hr in hair follicle biology.

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Figures

Figure 1
Figure 1
Skin; Hrrh-R/Hrrh-R mouse, 5 months old. Skin wrinkling is characteristic of rhino mutants of Hr.
Figure 2
Figure 2
Skin; Hrrh-R/Hrrh-R mouse, 4 weeks old. Scattered hair loss is readily visible at 4 weeks of age, occurring in a diffuse manner across the trunk.
Figure 3
Figure 3
Nail; Hrrh-R/Hrrh-R mouse, 6 months old. Nails are increasingly long and curved in Hrrh-R/Hrrh-R mice.
Figure 4
Figure 4
Skin; Hrrh-R/Hrrh-R mouse, 14 days old. Mouse dorsal skin from the interscapular region was sectioned and stained with HE. Infundibula were mildly ectatic and filled with laminated cornified cells (black arrow). The stratum granulosum extended from the epidermis to the entrance of the sebaceous gland duct. Bar: 20 μm.
Figure 5
Figure 5
Skin; Hrrh-R/+ mouse, 14 days old. Dorsal skin from the interscapular region was sectioned and stained with HE. The influndibulae (black arrow) were normal and lined by tight, compact squames that covered a thin-stratum granulosum with fine, dark basophilic granules. Bar: 20 μm.
Figure 6
Figure 6
Skin; Hrrh-R/Hrrh-R mouse, 18 days old. Dorsal skin from the interscapular region was sectioned and stained with HE. The influndibulae were ectatic and filled with more laminated cornified cells (black arrow) when compared to 14-day-old Hrrh-R/Hrrh-R mouse. The dilation also became larger. Bar: 20 μm.
Figure 7
Figure 7
Skin; Hrrh-R/+ mouse, 18 days old. Dorsal skin from the interscapular region was sectioned and stained with HE. The influndibulae appeared normal (black arrow). Bar: 20 μm.
Figure 8
Figure 8
Skin; Hrrh-R/Hrrh-R mouse, 21 days old. HE-stained section indicates a rim of keratinocytes surrounding the stranded dermal papilla (black arrow). Bar: 20 μm.
Figure 9
Figure 9
Skin; Hrrh-R/Hrrh-R mouse, 21 days old. HE-stained section indicates the ectatic infundibula filled with laminated cornified material (black arrow). Bar: 20 μm.
Figure 10
Figure 10
Skin; Hrrh-R/Hrrh-R mouse, 5 weeks old. HE-stained section indicates the epithelial connection (black arrow) between abnormal infundibulum and deep dermal cyst. Bar: 80 μm.
Figure 11
Figure 11
Skin; Hrrh-R/Hrrh-R mouse, 5 weeks old. Magnified HE-stained section indicates the epithelial connection (black arrow) between abnormal infundibulum and deep dermal cyst. Bar: 20 μm.
Figure 12
Figure 12
DNA sequence; Hrrh-R/Hrrh-R mouse, 4 weeks old. The electropherogram of DNA sequence around Hrrh-R mutation site in a homozygous mutant mouse (Hrrh-R/Hrrh-R). The arrow indicates the base mutanted in the mutant mice from C to T (3134C to T of NM_021877).
Figure 13
Figure 13
DNA sequence; wild-type mouse, 4 weeks old. The electropherogram of DNA sequence around Hrrh-R mutation site in a wild-type mouse (+/+). Arrow indicates that the base here is C (3134C in NM_021877).
Figure 14
Figure 14
DNA sequence; Hrrh-R/+ mouse, 4 weeks old. The electropherogram of DNA sequence around Hrrh-R mutation site in a heterozygous mouse (Hrrh-R/+). Arrow indicates that the base is changed from C to C/T in the heterozygotes (3134C in NM_021877).
Figure 15
Figure 15
RNA expression; effects of the mutation on Hr mRNA levels. Total RNA was extracted from dorsal skin of each genotype at different ages (1, 7, 14, 35 days after birth). A probe designed to span exon 12 of the Hr cDNA was amplified from wild-type skin cDNA using polymerase chain reaction. From the left side, lanes and samples are as follows: lane 1, 1 day, +/+; lane 2, 1 day, Hrrh-R/+; lane 3, 1 day, Hrrh-R/Hrrh-R; lane 4, 7 days, Hrrh-R/+; lane 5, 7 days, Hrrh-R/Hrrh-R; lane 6, 14 days, +/+; lane 7, 14 days, Hrrh-R/+; lane 8, 14 days, Hrrh-R/Hrrh-R; lane 9, 35 days, Hrrh-R/+; lane 10, 35 days, Hrrh-R/Hrrh-R. Arrow indicates the position of Hr transcript. The bottom panel represents the intensity of 28S rRNA from the ethidium bromide–stained gel as a loading control.
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