Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.

Mice that overexpress a mutated ornithine decarboxylase (ODC) transgene in outer root sheath keratinocytes of the hair follicle were used to study the role of this enzyme in regulating hair follicle structure and function. These transgenic mice have a normal first hair cycle, but lose their hair completely beginning 2-3 wk after birth. Transgene overexpression in follicular keratinocytes is first detected at day 12 after birth, coincident with the development of follicular cysts in the upper portion of the dermis. The onset of keratin 6 expression also begins around day 12; because the promoter/regulatory region of the bovine keratin 6 gene was used to target ODC transgene expression of hair follicle keratinocytes, these data demonstrate the faithful temporal and cell type-specific expression of the K6 -driven transgene. The ODC inhibitor 2-difluoromethylornithine could prevent hair loss and partially normalize skin histology if administered before the onset of ODC overexpression. 2-Difluoromethylornithine could also reactivate hair growth in animals with complete hair loss. Our results suggest that ODC is an important regulatory gene for the mouse hair follicle.

[1]  G. Rogers,et al.  Cyclic hair‐loss and regrowth in transgenic mice overexpressing an intermediate filament gene. , 1990, The EMBO journal.

[2]  B. Hogan,et al.  Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles. , 1993, Genes & development.

[3]  L. Hulbert,et al.  A new allele of the sparse fur gene in the mouse. , 1974, The Journal of heredity.

[4]  M. Ruggero,et al.  The Biology of Hearing and Deafness , 1988 .

[5]  T. Sun,et al.  Hair follicles, stem cells, and skin cancer. , 1993, The Journal of investigative dermatology.

[6]  M. Vidal,et al.  A 5'-upstream region of a bovine keratin 6 gene confers tissue-specific expression and hyperproliferation-related induction in transgenic mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  T. Slaga,et al.  alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Demars,et al.  Abnormal ornithine carbamoyltransferase in mice having the sparse-fur mutation. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Mann.  Hair loss and cyst formation in hairless and rhino mutant mice , 1971, The Anatomical record.

[10]  T G O'Brien,et al.  Constitutively elevated levels of ornithine and polyamines in mouse epidermal papillomas. , 1991, Carcinogenesis.

[11]  R. Boutwell,et al.  Induction of the polyamine-biosynthetic enzymes in mouse epidermis by tumor-promoting agents. , 1975, Cancer research.

[12]  P. McCann,et al.  Inhibition of ornithine decarboxylase with 2-difluoromethylornithine: reduced incidence of dimethylhydrazine-induced colon tumors in mice. , 1983, Cancer research.

[13]  W. Franke,et al.  The complement of native alpha-keratin polypeptides of hair-forming cells: a subset of eight polypeptides that differ from epithelial cytokeratins. , 1986, Differentiation; research in biological diversity.

[14]  T G O'Brien,et al.  The induction of ornithine decarboxylase as an early, possibly obligatory, event in mouse skin carcinogenesis. , 1976, Cancer research.

[15]  M. Takigawa,et al.  Polyamine biosynthesis and skin tumor promotion: inhibition of 12-O-tetradecanoylphorbol-13-acetate-promoted mouse skin tumor formation by the irreversible inhibitor of ornithine decarboxylase alpha-difluoromethylornithine. , 1982, Biochemical and biophysical research communications.

[16]  M. Blessing,et al.  Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase. , 1995, Cancer research.

[17]  M. Gossen,et al.  Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Boutwell,et al.  Induction of the polyamine-biosynthetic enzymes in mouse epidermis and their specificity for tumor promotion. , 1975, Cancer research.

[19]  G. Wilding,et al.  Randomized Phase I Chemoprevention Dose-Seeking Study of α-Difluoromethylornithine , 1993 .

[20]  G. Martin,et al.  FGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations , 1994, Cell.