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WIREs Dev Biol
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Module‐based complexity formation: periodic patterning in feathers and hairs

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Abstract Patterns describe order which emerges from homogeneity. Complex patterns on the integument are striking because of their visibility throughout an organism's lifespan. Periodic patterning is an effective design because the ensemble of hair or feather follicles (modules) allows the generation of complexity, including regional variations and cyclic regeneration, giving the skin appendages a new lease on life. Spatial patterns include the arrangements of feathers and hairs in specific number, size, and spacing. We explore how a field of equivalent progenitor cells can generate periodically arranged modules based on genetic information, physical–chemical rules and developmental timing. Reconstitution experiments suggest a competitive equilibrium regulated by activators/inhibitors involving Turing reaction‐diffusion. Temporal patterns result from oscillating stem cell activities within each module (microenvironment regulation), reflected as growth (anagen) and resting (telogen) phases during the cycling of feather and hair follicles. Stimulating modules with activators initiates the spread of regenerative hair waves, while global inhibitors outside each module (macroenvironment) prevent this. Different wave patterns can be simulated by cellular automata principles. Hormonal status and seasonal changes can modulate appendage phenotypes, leading to ‘organ metamorphosis’, with multiple ectodermal organ phenotypes generated from the same precursors. We discuss potential novel evolutionary steps using this module‐based complexity in several amniote integument organs, exemplified by the spectacular peacock feather pattern. We thus explore the application of the acquired knowledge of patterning in tissue engineering. New hair follicles can be generated after wounding. Hairs and feathers can be reconstituted through self‐organization of dissociated progenitor cells. WIREs Dev Biol 2013, 2:97–112. doi: 10.1002/wdev.74 This article is categorized under: Establishment of Spatial and Temporal Patterns > Repeating Patterns and Lateral Inhibition Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing

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(a) Schematic illustration of hair cycling in a population of hair follicles. (b) A 2D cellular automata (CA) model can predict regenerative patterns in a large population of hair SCs. Skin pigmentation patterns result from color changes of many HFs when they collectively cycle through four phases: P (blue)→A (yellow)→R (red)→C (green). Distinct hypothetical activator/inhibitor signaling profiles can be assigned to all four phases. (c) Cellular automata (CA) model for the observed hair wave. Wiggly white lines indicate the spreading of the hair wave from hairs in propagating anagen to hairs in competent telogen, whereas hairs in autonomous anagen or propagating anagen cannot initiate the hair cycle in hair follicles that are in refractory telogen. (d) Hair follicles may regenerate in response to intrinsic signals which drive each individual follicle or to extrinsic signals which can couple the activation of the hair cycle in neighboring follicles. By modulating the strength of intrinsic stem cell (SC) activation (Y‐axis) and the probability of coupled activation (X‐axis), different animals or different physiological conditions in the same animal can significantly alter the global dynamics of hair regeneration. As a result, versatile hair growth patterns in rabbits, mice, normal and alopecic human scalps can be explained within the same patterning framework based simply on how hair SC activities are ‘managed’. (Panels b, c, and d are reprinted with permission from Ref 7. Copyright 2011 American Association for the Advancement of Science)

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Cellular and molecular events during periodic formation of feather primordia. (a–a′′′) In situ hybridization for β‐catenin demonstrates a restrictive expression pattern. (a′′) In normal chicken skin development there is moderate staining in each of the feather tracts. As feather buds form, staining increases in the buds and decreases in the surrounding interbud region. The pattern appears normal in scaleless chickens at stage 29 (a′) but fails to progress in a restrictive manner at stage 30 (a′′′). (b) In the femoral tract, the β‐catenin‐free spacing between buds increases over time. (c) Schematic of increasing feather bud spacing during early stages of feather morphogenesis. (Reprinted with permission from Ref 24 and 28. Copyright 2000 Elsevier) (d) pERK immunostaining in chicken embryos from stage 29, 32 and 35. (Reprinted with permission from Refs 28. Copyright 2009 Elsevier) pERK also demonstrates a restrictive expression pattern. (e) Schematic of early‐acting global and later early events during feather morphogenesis. (Reprinted with permission from Ref 2. Copyright 2004 UBC Press) (f) Reconstituting skin explants showed that the size of the feather buds increased with increasing numbers of dissociated mesenchymal fibroblasts. Approximately equal spacing between buds was observed. (g) Model depicting how the relative activator/inhibitor activities regulate feather bud size and spacing. (Reprinted with permission from Ref 21. Copyright 1999 The Company of Biologists, Ltd.)

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(a) Diagram depicting how repetitive primordia in different regions can serve as ‘modules’ and assume different characteristics. Through a process akin to metamorphosis that occurs at the organ level they can develop into different ectodermal organs. Individually they undergo temporal cycling and as a population can form a regenerative wave. (b) A peacock shows the stunning complex skin appendage pattern occurring in feather size, shape, arrangement, and pigmentation. These are also sexually dimorphic. Feather patterning uses all the module variation principles discussed here.

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Representatives of feathered dinosaurs and Mesozoic birds from Jehol Biota. (a) Map showing the location of the excavated site. (b) Sinosauropteryx. (c) Sinornithosaurus. (d) Caudipteryx. (e) Microraptor gui. (f) Confuciusornis. (Panels b–d are reprinted with permission from Ref 75. Copyright 1998 National Geographic Society. Panel e is reprinted with permission from Ref 76. Copyright 2003 Nature Publishing Group. Panel f is reprinted with permission from Ref 77. Copyright 2003 Yunnan Science and Technology). (g) Longirostrornis fossil, primarily in dorsal view. Inset, close‐up of beak and teeth. (h) Model of branching morphogenesis responsible for radial versus bilateral symmetric feathers based on feather cross sections. It shows that the barb ridge formation is basically a periodic patterning process. See text for more. (i) Schematic depicting the tilting of feather stem cell ring (orange color) leads to the symmetric breaking at ramogenic zone (region where periodic patterning of barb ridges takes place, blue color), thus making radial versus bilateral symmetric feathers.

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(a) Homogeneously distributed cells through random interactions form unstable aggregates. This forms random variations which are amplified above a threshold at which the patterns become set. Distinct patterns are formed by competition between intrinsic factors (properties of the membranes and extracellular matrix), concentrations of activators and inhibitors, and the size of the primordia field. (Reprinted with permission from Ref 2. Copyright 2004 UBC Press) (b) Feathers from two similarly aged chicken embryos demonstrate stochasticity in the placement of feather buds. The feathers show a similar yet nonidentical pattern. Numbers of feathers in each region are indicated. Yellow dots highlight feathers along the midline. Green dots highlight subsequent feather buds. Red dots show the relative position of sequential feather buds.

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(a) Schematic summary showing the periodic patterning process during feather morphogenesis. Epithelial–mesenchymal signaling fosters the formation of competent epithelium. Spatially distributed activators and inhibitors of feather formation promote the expression of adhesion molecules which lead to the formation of unstable microaggregates. In these early stages, FGF acts as an activator while BMP acts as an inhibitor. The expression of FGF/pERK later promotes chemotaxis toward a signaling center in this patterning process leading to the formation of stable epithelial placodes and dermal condensations. The placode boundary is unstable at fitow but then becomes stabilized. (Reprinted with permission from Refs 28. Copyright 2009 Elsevier) (b) Schematic drawing of the hair reconstitution procedure. Green, epidermal cells; red, dermal cells. Cells are mixed randomly in the 3D matrix. Epidermal cells sort themselves out and coalesce to form a layer first near the bottom of the matrix which then rises to the top surface. Dermal cells form condensations adjacent to the epidermis. Hair germs appear periodically and progress to form hair pegs and later, hair follicles. The morphogenetic process occurs between about day 5 to 12 after grafting. (c) Reconstituted hair follicles form normally. Using a reasonably stiff matrix to hold multipotential cells, the graft can be cut to specific shapes and sizes for cosmetic applications. Panels b and c are from Ref 81. Copyright 2011 Mary Ann Liebert Publishers, Inc.)

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Establishment of Spatial and Temporal Patterns > Repeating Patterns and Lateral Inhibition
Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing