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Scientists have developed a mouse model of inherited baldness, which they anticipate will further the current understanding of the molecular mechanisms underlying human hair loss.
The report is published in the June 1 issue of the scientific journal Genes & Development.
Dr. Pierre Coulombe and colleagues at Johns Hopkins School of Medicine (Maryland) and the CNRS-Institut Pasteur (France) have genetically engineered mice to lack a gene that encodes a keratin protein. Keratins are structural proteins found in all epithelia including the hair, nails and epidermis of humans, as well as the fur, feathers and hooves of animals. Of the nearly thirty keratin genes expressed in hair follicles, Dr. Coulombe and colleagues found that a deficiency in just one – keratin 17 – causes temporary baldness in mice.
Dr. Coulombe and colleagues generated keratin 17 (K17)-deficient mice, or K17 knockout mice, in order to define the function of the keratin 17 protein. They found that K17 knockout mice appear normal at birth, but within a few days display a peculiar hair phenotype. Whereas normal newborn mice develop their characteristic fur coat within 3-7 days after birth, a portion of newborn K17-deficient mice do not grow fur at all within the first few weeks of their lives.
Dr. Coulombe and colleagues determined that the cause of alopecia, or baldness, in these K17 knockout mice is severe hair fragility and premature death of hair-producing cells, thereby establishing keratin 17 as a crucial factor in the normal emergence of hair early after birth. Although the severity of alopecia was variable in the K17 knockout mice, one key featured emerged: Regardless of how severely afflicted the K17-deficient mice were, at about three weeks old, all of the mice began to grow fur.
The researchers noted that this dramatic change correlates with the beginning of a new, postnatal hair growth cycle, suggesting that keratin 17 activity becomes less crucial in the adult hair cycle, and/or other genes help to modify the effects of keratin 17 loss at this point. This, coupled with the overall variation in hair phenotype and lack of abnormalities in other tissues that normally express keratin 17, prompted Dr. Coulombe and colleagues to investigate what other genes could be compensating for the loss of keratin 17 activity.
They discovered that a closely related keratin gene, keratin 16, is, indeed, activated in response to keratin 17 loss and therefore may help alleviate baldness in K17 knockout mice.
The phenotypic variability exhibited by K17-deficient mice may help explain the clinical heterogeneity inherent to a subset of human keratin-based skin disorders. Inherited mutations in the human keratin 17 gene cause two separate epithelial disorders related to ectodermal dysplasias. Although each disorder is mainly characterized by different epithelial anomolies, both share a predisposition for hair follicle abnormalities. Furthermore, the hair abnormalities that occur in people with inherited K17 mutations vary both in frequency and severity – just like those in K17 knockout mice.
As Dr. Coulombe explains, this work represents a marked advance because "not only are the features of these mice very informative with regards to how hair tissue works and the role of keratin proteins in hair structure and growth, it also provides significant insight into the clinical heterogeneity of the skin diseases arising as a result of inherited mutations in the keratin 17 gene."
Further research is needed to determine precisely how specific keratin proteins such as keratin 16 and keratin 17 impact so profoundly on the biology of hair follicles and related epithelial tissues.
Journal
Genes & Development