First described by Darwin in 1875 as a condition affecting the 'toothless men of Sind'—members of a Hindu kindred from the Hyderabad region of India—hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the teeth, hair and sweat glands.

Three mouse lines, Tabby (Ta), Crinkled (cr) and Downless (dl), show the same phenotype as HED, and Overbeek and colleagues have now cloned the dl gene using a classic positional cloning approach, as described in the August issue of Nature Genetics.

They report that the dl expression pattern changes from being uniform in the basal cells of the epidermis to being restricted to placodes during follicular morphogenesis.

The figure shows in situ hybridization of dl on an Ove951 mouse embryo at day 15. Epidermal placodes begin to form on the trunk by day 14, and distinct waves of new follicle formation occur until a few days after birth. Placodes are clearly visible as scattered, regularly spaced dots. The low level of expression in the surrounding cells suggests that a complex form of inductive and inhibitory signals is responsible for epithelial patterning.

Based on sequence similarities, the protein encoded at the dl locus is thought to encode a tumor necrosis factor-like transmembrane receptor. In fact, Tabby cDNA has been cloned recently, and sequence analysis shows it has homology to the tumor necrosis factor family, indicating that the product of Ta could be a dl ligand. Moreover the human homolog of Ta has been found mutated in the X-linked form of HED. A new signaling pathway responsible for cell induction and hair follicle cell fate seems to emerge.

In the same issue of Nature Genetics, Monreal et al. report the identification of dl human homolog mutations in three HED families. So now the race is on to clone Crinkled.