Date of Award

5-2006

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Brynn H. Voy

Committee Members

Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich

Abstract

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 homozygotes mutant, called near naked hairless (Hrn), never develops a normal coat, while heterozygotes display a sparse coat and become completely nude as they age. The Hrn/Hrn mutant mice are significantly smaller in body size and have very short, curly, and few vibrissae. Histological analysis revealed premature keratinization in the precortical region of hair follicles, formation of mineralized dermal cysts, and loss of hair follicles. Adult heterozygotes display pili multigemini (i.e. more than one hair from one piliary canal) after the first hair cycle, suggesting abnormal regulation of hair shaft formation by the mutation. A mutation was not identified in the coding region of Hr nor in candidate genes around Hr, suggesting a possible regulatory mutation of Hr. Microarray analysis was used to survey the gene expression profile and to identify the molecular mechanisms altered by the Hrn mutation. Several pathways including Wnt/β-catenin, TGF-β, and apoptosis are significantly altered in Hrn mutants, indicating the involvement of Hrn in these pathways. Hrn mutant mice are also suggested to be a research model for human MUHH (Marie Unna Hereditary Hypotrichosis).

The second mouse mutant, called rhino-like (HrrhR), 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, the formation of dermal cysts, and the destruction of hair follicles. Since the phenotype in the homozygous mutants is very close to that in Hrrh mutant mice, the genomic DNA of Hr gene was directly sequenced. A nonsense mutation was identified in the exon 12, leading to significantly reduced Hr expression, probably due to nonsense-mediated decay. The allele was named as rhino in Oak Ridge with the symbol HrrhR (R for Oak Ridge). Microarray analysis of skin from mice at 7, 10, and 35 days was applied to identify the downstream events of the HrrhR mutation. Several genes including Krt1-10, Krt2-1, IL-17, and Itgb4, were identified as the potential targets of HrrhR. Wnt/β-catenin, apoptosis, and ERK/MAPK signaling pathways were altered in HrrhR/HrrhR mutant mice, suggesting a possible role of Hr to regulate these pathways. Microarray analysis also shows many immune-related genes with differential expression, indicating the possible involvement of Hr in immune response. 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.

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