Regenerative metamorphosis in hairs and feathers: follicle as a programmable biological printer

Present-day hairs and feathers are marvels of biological engineering perfected over 200 million years of convergent evolution. Prominently, both follicle types coevolved regenerative cycling, wherein active filament making (anagen) is intermitted by a phase of relative quiescence (telogen). Such regenerative cycling enables follicles to “reload” their morphogenetic program and make qualitatively different filaments in the consecutive cycles. Indeed, many species of mammals and birds undergo regenerative metamorphosis, prominently changing their integument between juvenile and adult forms. This phenomenon is inconspicuous in mice, which led to the conventional perception that hair type is hardwired during follicle morphogenesis and cannot switch. A series of recent works by Chi and Morgan change this perception, and show that many mouse follicles naturally switch hair morphologies, for instance from “wavy” zigzag to straight awl, in the second growth cycle. A series of observations and genetic experiments show that back and forth hair type switching depends on the number of cells in the follicle's dermal papilla, with the critical threshold being around 40-50 cells. Pigmentation is another parameter that hair and feather follicles can reload between cycles, and even midway through anagen. Recent works show that hair and feather pigmentation “printing” programs coevolved to rely on pulsed expression of Agouti, a melanocortin receptor-1 antagonist, in the follicular mesenchyme. Here, we discuss broader implications of hair and feather regenerative plasticity.