In 2004 a group of researchers led by Jeremy Nathans, a geneticist and molecular biologist at the Johns Hopkins School of Medicine, discovered that mutant mice, missing a gene that codes for the protein frizzled 6, had unruly waves and tufts of hair rather than neatly ordered pelts. The scientists noticed they could tell the mice apart by their paws: The paw hairs of wild mice all point toward the digits from the heel, whereas the knockout mice exhibited a counterclockwise whorl of hair on their left paws and a clockwise whorl of hair on their right ones. The hairs on the heads of the normal mice pointed toward their noses from their necks; the hairs on the heads of mice missing frizzled 6, however, fell in different ways. "There's something variable from animal to animal," Nathan notes, "even though they carry the same mutation."
In an effort to find a cause for this randomness, the researchers observed 24 wild and 27 mutant mice daily between birth and the time their hair first penetrated the surfaces of their skin, noting how the macroscopic pattern of the hair changed. Normal mice had uniform follicle angles (ranging from 40 degrees to 45 degrees) on their paws and backs. The mutants appeared to have completely random orientations from birth. By quantitatively analyzing the angles of the follicle shafts, Nathans found that all the mice locally refined their distributions, though the mutant mice seemed to undergo much more drastic realignment. "The inference would be that the frizzled 6 gene is involved in the global process only," Nathans explains, "but the local process remains unaffected."
So, in the first step of the two-part development mechanism, frizzled 6 determines whether the follicles will be randomly scattered or orderly. Nathans likens the movement of hair follicles during the second step of the process to iron filings lining up when under the influence of ferromagnets: "The reason they're lined up is because the spins in each iron atom interact with the spins of adjacent iron atoms and there's a favorable energy to having them aligned and a disfavorable energy to having them not aligned," Nathans says. Likewise, "each follicle is somehow influenced by its immediate neighbors to change its orientation to increasingly approximate the average over its neighbors."
Nathans believes a similar mechanism governs the alignment of scales on fish and reptiles as well as feathers on a bird. "If you're off by five degrees," he says, "you'll have a huge Darwinian lack of fitness in terms of flying speed, maneuverability or insulation, for example." Paul Adler, a biologist at the University of Virginia, notes that the two-step, refinement mechanism also governs single-celled hairs in drosophila fruit flies. "It makes good biological sense that you don't try and make something perfect with one mechanism," Adler says. "You first get it roughly aligned and then use an independent mechanism for making it more aligned."
As to whether this is also the mechanism that confers straight, ordered hair in humans, Nathans notes, "It's almost certainly going on in us just because all the genes in this mouse pathway are virtually identical in humans."