413 Epidermal dysplasia and hair defects in the disheveled hair and ears (LmnaDhe) mouse

Abstract

412 Hairless (Hr) mutations and phenotypes: The new and the old J Cook, CH Pratt, D Bikle, RH Rice, MV Wiles and JP Sundberg 1 The Jackson Laboratory, Bar Harbor, ME, 2 Environmental Toxicology, University of California, Davis, CA and 3 Dermatology and Medicine, University of California, San Francisco, CA Hairless mice were first described over 150 years ago in the form of the severe rhino mouse mutation (Hr) closely followed by a more mild phenotypic allele named hairless (Hr). Eventually both these alleles were established in both inbred and outbred mouse colonies. About 30 years ago these mice, primarily the hairless allele as it was called with the milder phenotype, became commonly used for skin cancer research, both UV light and chemical carcinogen induced, as the mice lacked hair as adults and were considered by many to be useful models of normal human skin. Subsequently, it was found that the Hr was a good model of papular atrichia. Today, there is a rich, but possibly confusing, landscape of different mutantHr alleles present on a multitude of inbred, outbred, congenic, and segregating mouse strains. To confound this problem further there are also a number of mutant Hr phenocopies, i.e. mouse strains with mutations in genes that mimic the hairless phenotype, such as mutant alleles in the Vdr, Odc1, and other genes in the putrescine pathway. In this overview, we will clarify the phenotypes, genotypes, and mouse strain considerations that need to be accounted for when designing a study and interpreting the results of studies using these mice including many new alleles, both spontaneous and genetically engineered. 413 Epidermal dysplasia and hair defects in the disheveled hair and ears (Lmna) mouse CH Pratt, J Cook and JP Sundberg The Jackson Laboratory, Bar Harbor, ME Lamin A is one component of the nuclear lamina, a chromatin-binding network of type V intermediate filaments, including Lamin C, B1 and B2 which together form a proteinaceous boundary to the nucleus. The Lmna/LMNA gene has over 200 known miss-sense mutations that cause a range of disease phenotypes including progeria, muscular dystrophy, lipodystrophy, and cardiomyopathy. Human patients with mutations in the LMNA gene have a variety of skin abnormalities as does the semi-dominant, spontaneous mutation in the mouse called Disheveled hair and ears (Lmna). Ten day old Lmna/Lmna mice present with a markedly thickened dysplastic epidermis with scattered interfollicular pigmentation, multinucleated kertinocytes, and dystrophic hair follicles when compared to control littermates. The dysplastic epidermis aberrantly expressed mouse specific keratin 6, a nonspecific marker of hyperplasia and neoplasia, associated with downregulation of keratins 1 and 10. The stratum granulosum was thickened with increased expression of filaggrin and loricrin. Expression patterns were normal in wild type and heterozygous mice. Scanning electron microscopy and energy-dispersive X-ray spectroscopy revealed defects in hair shafts associated with low sulfur content of hair in Lmna/Lmna but not in +/+ or +/ Lmna mice. The Lmna mutation in mice causes marked epidermal dysplasia suggesting that mutations in Lmna may play an important role in cutaneous squamous cell carcinoma and possibly other types of skin cancer.