18th International Mouse Genome Conference
17-22 October 2004, Seattle, USA
Plenary Presentations * Oral
Presentations * Poster
Abstracts * Photos
Verne Chapman Memorial Lecture * Table
of Contents * Attendees * Awards
POSTER 53 - IDENTIFICATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DEVELOPMENT OF HAIRLESS PHENOTYPE IN NEAR NAKED HAIRLESS (HRN) MICE
Liu YT 1, Das S 2, Olszewski RE 2, Lu XC 3, Voy BH 2
1 University of Tennessee, Knoxville, United States, 2 Oak Ridge National Lab, Oak Ridge, United States,
3 Lawrence Livermore National Laboratory, Livermore, United States
Recessive mutations at the mouse hairless (hr) locus cause hair loss and increased susceptibility to chemical and UV carcinogenesis. The near naked (Hrn) allele of hr arose spontaneously in the ORNL mouse colony and is unique in both its mode of inheritance (semi-dominant) and in the fact that, unlike recessive mutations that lead to hair loss after the first hair cycle, affected animals never grow a normal coat. The hr gene encodes a transcriptional repressor, but little is known about the cellular pathways in which it acts. We are therefore characterizing the Hrn mutation and using cDNA microarrays and histology to identify early changes in gene expression and skin structure that coincide with phenotype development and precede epidermal lesions that occur in adult animals. Northern blot analysis and PCR of the hr cDNA indicated normal transcript size and exon composition. We sequenced the open reading frame and the 5’- and 3’- UTRs in Hrn/Hrn mice and in both potential founder strains (C3H and 101), but we did not identify any base pair changes in mutant animals. Quantitative RT-PCR analysis indicated differential hr expression in mutant mice. In adults, hr expression was down-regulated by approximately two- and seven-fold in heterozygous and homozygous animals, respectively. However at seven days of age, the age at which mutant animals are phenotypically distinguishable from wild type littermates, hr expression was elevated (2-fold in Hrn/+ and 3-fold in Hrn/ Hrn, respectively, vs. +/+). These differences were confirmed with Northern blots. Combined, these data suggest a potential regulatory rather than coding region mutation in Hrn mice. Microarray analysis of skin from adult animals identified a set of genes that were differentially expressed in Hrn/+ compared to +/+. Approximately 80% of the genes indicated as disregulated by microarray were confirmed by real time RT-PCR and were also shown to be altered in 7-day old animals. Many of these genes encode keratin-associated proteins, which provide structural support to the hair fiber matrix. Given histological analysis indicating an early defect in hair structure, the early nature of changes in gene expression relative to phenotype development, and the fact that hr encodes a transcription factor, we predict that genes critical for proper hair formation are primary targets of hr, and that their normal expression levels are disrupted by abundance of hr protein.