Molecular and physiological basis for hair loss in near naked hairless and oak ridge rhino-like mouse models: Tracking the role of the Hairless gene

Hairless mice have been widely used in basic research and clinical trials. Two new mouse mutants with hair loss arose spontaneously in the breeding colony of Oak Ridge National Laboratory. The first one is called near naked hairless (Hrn). The homozygotes never develop the normal coat, while the heterozygotes display a sparser coat, which become more severe with age. The homozygotes have retarded growth and curly, very short, and few vibrissae. Premature keratinization in hair follicles and formation of mineralized dermal cysts were found in the homozygotes. Adult heterozygotes display pili multigemini (i.e. more than one hair from one piliary canal), suggesting abnormal regulation of hair shaft formation. A mutation was not identified in Hr, suggesting a possible regulatory mutation of Hr. Microarray analysis was used to profile the gene expression and to identify the molecular mechanisms altered by Hrn mutation. Several pathways including wnt/beta-catenin, TGF-beta, and apoptosis are significantly altered in Hr n mutants. Hrn mutant mice were also suggested to be a research model for Marie Unna Heritary Hypotrichosis in human patients. The second mutant, called rhino-like (Hr rhr), displays progressive and random hair loss and wrinkling skin, leading to a rhinocerotic appearance. Histological analysis revealed the formation of utricles at as early as 10 days of age and the formation of dermal cysts and the destruction of hair follicles. A nonsense mutation was identified in the exon 12 of Hr. Hr expression was dramatically reduced in the homozygotes. Microarray analysis of skin from mice at 7, 10, and 35 days was applied to identify the downstream events of Hr rhR mutation. Several genes including Krt1-10, Krt2-1, IL-17, and Itgb4, were identified as potential targets of HrrhR. Wnt/beta-catenin, apoptosis, and ERK/MAPK signaling pathways are altered in HrrhR/Hr rhR mutant mice, suggesting a possible role of Hr to regulate these pathways. Microarray analysis shows many immune-related genes with differential expression, indicating the possible involvement of Hr in immune function. Identification of this new Hr allele and its related research allows further understanding about the function of Hr and the mechanisms of alopecia, i.e. hair loss.