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ABSTRACT: Alopecia can be caused by defective formation, defective regeneration, or increased destruction of hair follicles. Much work has elucidated the roles of diffusible morphogens in modulating hair follicle stem cell activities. Recent studies have revealed novel molecular events within the nucleus, which are required for the activation and progression of hair stem cells. These studies will provide new clues and targets for designing therapeutic strategies for hair loss.
Journal of Investigative Dermatology 06/2013; 133(6):1450-1452. · 6.31 Impact Factor
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Ping Wu,
Xiaoshan Wu, Ting-Xin Jiang,
Ruth M Elsey,
Bradley L Temple,
Stephen J Divers,
Travis C Glenn,
Kuo Yuan,
Min-Huey Chen,
Randall B Widelitz,
Cheng-Ming Chuong
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ABSTRACT: Reptiles and fish have robust regenerative powers for tooth renewal. However, extant mammals can either renew their teeth one time (diphyodont dentition) or not at all (monophyodont dentition). Humans replace their milk teeth with permanent teeth and then lose their ability for tooth renewal. Here, we study tooth renewal in a crocodilian model, the American alligator, which has well-organized teeth similar to mammals but can still undergo life-long renewal. Each alligator tooth is a complex family unit composed of the functional tooth, successional tooth, and dental lamina. Using multiple mitotic labeling, we map putative stem cells to the distal enlarged bulge of the dental lamina that contains quiescent odontogenic progenitors that can be activated during physiological exfoliation or artificial extraction. Tooth cycle initiation correlates with β-catenin activation and soluble frizzled-related protein 1 disappearance in the bulge. The dermal niche adjacent to the dermal lamina dynamically expresses neural cell adhesion molecule, tenascin-C, and other molecules. Furthermore, in development, asymmetric β-catenin localization leads to the formation of a heterochronous and complex tooth family unit configuration. Understanding how these signaling molecules interact in tooth development in this model may help us to learn how to stimulate growth of adult teeth in mammals.
Proceedings of the National Academy of Sciences 05/2013; · 9.68 Impact Factor
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ABSTRACT: How organs are shaped to specific forms is a fundamental issue in developmental biology. To address this question, we used the repetitive, periodic pattern of feather morphogenesis on chicken skin as a model. Avian feathers within a single tract extend from dome-shaped primordia to thin conical structures with a common axis of orientation. From a systems biology perspective, the process is precise and robust. Using tissue transplantation assays, we demonstrate that a "zone of polarizing activity," localized in the posterior feather bud, is necessary and sufficient to mediate the directional elongation. This region contains a spatially well-defined nuclear β-catenin zone, which is induced by wingless-int (Wnt)7a protein diffusing in from posterior bud epithelium. Misexpressing nuclear β-catenin randomizes feather polarity. This dermal nuclear β-catenin zone, surrounded by Notch1 positive dermal cells, induces Jagged1. Inhibition of Notch signaling disrupts the spatial configuration of the nuclear β-catenin zone and leads to randomized feather polarity. Mathematical modeling predicts that lateral inhibition, mediated by Notch signaling, functions to reduce Wnt7a gradient variations and fluctuations to form the sharp boundary observed for the dermal β-catenin zone. This zone is also enriched for nonmuscle myosin IIB. Suppressing nonmuscle myosin IIB disrupts directional cell rearrangements and abolishes feather bud elongation. These data suggest that a unique molecular module involving chemical-mechanical coupling converts a pliable chemical gradient to a precise domain, ready for subsequent mechanical action, thus defining the position, boundary, and duration of localized morphogenetic activity that molds the shape of growing organs.
Proceedings of the National Academy of Sciences 04/2013; · 9.68 Impact Factor
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ABSTRACT: Introduction: There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate, and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration, and potential therapeutic opportunities these advances may offer. Areas covered: Here, we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories: i) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. ii) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. iii) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. iv) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair-forming competent epidermal cells and hair-inducing dermal cells. Expert opinion: Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials.
Expert opinion on biological therapy 01/2013; · 3.22 Impact Factor
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ABSTRACT: In the process of organogenesis, different cell types form organized tissues and tissues are integrated into an organ. Most organs form in the developmental stage, but new organs can also form in physiological states or following injuries during adulthood. Feathers are a good model to study post-natal organogenesis because they regenerate episodically under physiological conditions and in response to injuries such as plucking. Epidermal stem cells in the collar can respond to activation signals. Dermal papilla located at the follicle base controls the regenerative process. Adhesion molecules (e.g., neural cell adhesion molecule (NCAM), tenascin), morphogens (e.g., Wnt3a, sprouty, fibroblast growth factor [FGF]10), and differentiation markers (e.g., keratins) are expressed dynamically in initiation, growth and resting phases of the feather cycle. Epidermal cells are shaped into different feather morphologies based on the molecular micro-environment at the moment of morphogenesis. Chicken feather variants provide a rich resource for us to identify genetic determinants involved in feather regeneration and morphogenesis. An example of using genome-wide single nucleotide polymorphism (SNP) analysis to identify alpha keratin 75 as the mutation in frizzled chickens is demonstrated. Due to its accessibility to experimental manipulation and observation, results of regeneration can be analyzed in a comprehensive way. The layout of time dimension along the distal (formed earlier) to proximal (formed later) feather axis makes the morphological analyses easier. Therefore feather regeneration can be a unique model for understanding organogenesis: from activation of stem cells under various physiological conditions to serving as the Rosetta stone for deciphering the language of morphogenesis.
Embryologia 01/2013; 55(1):139-48. · 2.21 Impact Factor
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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 specified 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 (micro-environment 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 (macro-environment) 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 evolutionary novel 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.
Wiley interdisciplinary reviews. Developmental biology. 01/2013; 2(1):97-112.
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ABSTRACT: To examine the roles of epigenetic modulation on hair follicle regeneration, we generated mice with a K14-Cre-mediated loss of DNA methyltransferase 1 (DNMT1). The mutant shows an uneven epidermal thickness and alterations in hair follicle size. When formed, hair follicle architecture and differentiation appear normal. Hair subtypes exist but hair fibers are shorter and thinner. Hair numbers appear normal at birth but gradually decrease to <50% of control in 1-year-old mice. Sections of old mutant skin show follicles in prolonged telogen with hyperplastic sebaceous glands. Anagen follicles in mutants exhibit decreased proliferation and increased apoptosis in matrix transient-amplifying cells. Although K15-positive stem cells in the mutant bulge are comparable in number to the control, their ability to proliferate and become activated to form a hair germ is reduced. As mice age, residual DNMT activity declines further, and the probability of successful anagen reentry decreases, leading to progressive alopecia. Paradoxically, there is increased proliferation in the epidermis, which also shows aberrant differentiation. These results highlight the importance of DNA methylation in maintaining stem cell homeostasis during the development and regeneration of ectodermal organs.Journal of Investigative Dermatology advance online publication, 5 July 2012; doi:10.1038/jid.2012.206.
Journal of Investigative Dermatology 07/2012; · 6.31 Impact Factor
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ABSTRACT: The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.
Physiology 04/2012; 27(2):61-72.
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ABSTRACT: The ephrin receptor (Eph) tyrosine kinases and their ephrin ligands are involved in morphogenesis during organ formation. We studied their role in feather morphogenesis, focusing on ephrin-B1 and its receptor EphB3. Early in feather development, ephrin-B1 mRNA and protein were found to be expressed in the dermal condensation, but not in the inter-bud mesenchyme. Later, in feather buds, expression was found in both the epithelium and mesenchyme. In the feather follicle, ephrin-B1 protein expression was found to be enriched in the feather filament epithelium and in the marginal plate which sets the boundary between the barb ridges. EphB3 mRNA was also expressed in epithelia. In the feather bud, its expression was restricted to the posterior bud. In the follicle, its expression formed a circle at the bud base which may set the boundary between bud and inter-bud domains. Perturbation with ephrin-B1/Fc altered feather primordia segregation and feather bud elongation. Analyses revealed that ephrin-B1/Fc caused three types of changes: blurred placode boundaries with loose dermal condensations, incomplete follicle invagination with less compact dermal papillae, and aberrant barb ridge patterning in feather filament morphogenesis. Thus, while ephrin-B1 suppression does not inhibit the initial emergence of a new epithelial domain, Eph/ephrin-B1 interaction is required for its proper completion. Consequently, we propose that interaction between ephrin-B1 and its receptor is involved in boundary stabilization during feather morphogenesis.
The International journal of developmental biology 01/2012; 56(9):719-28. · 2.16 Impact Factor
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ABSTRACT: Organogenesis involves a series of dynamic morphogenesis and remodeling processes. Since feathers exhibit complex forms, we have been using the feather as a model to analyze how molecular pathways and cellular events are used. While several major molecular pathways have been studied, the roles of matrix degrading proteases and inhibitors in feather morphogenesis are unknown. Here we addressed this knowledge gap by studying the temporal and spatial expression of proteases and inhibitors in developing feathers using mammalian antibodies that cross react with chicken proteins. We also investigated the effect of protease inhibitors on feather development employing an in vitro feather bud culture system. The results show that antibodies specific for mammalian MMP2 and TIMP2 stained positive in both feather epithelium and mesenchyme. The staining co-localized in structures of E10-E13 developing feathers. Interestingly, MMP2 and TIMP2 exhibited a complementary staining pattern in developing E15 and E20 feathers and in maturing feather filaments. Although they exhibited a slight delay in feather bud development, similar patterns of MMP2 and TIMP2 staining were observed in in vitro culture explants. The broad spectrum pharmacological inhibitors AG3340 and BB103 (MMP inhibitors) but not Aprotinin (a plasmin inhibitor) showed a reversible effect on epithelium invagination and feather bud elongation. TIMP2, a physiological inhibitor to MMPs, exhibited a similar effect. Markers of feather morphogenesis showed that MMP activity was required for both epithelium invagination and mesenchymal cell proliferation. Inhibition of MMP activity led to an overall delay in the expression of molecules that regulate either early feather bud growth and/or differentiation and thereby produced abnormal buds with incomplete follicle formation. This work demonstrates that MMPs and their inhibitors are not only important in injury repair, but also in development tissue remodeling as demonstrated here for the formation of feather follicles.
Differentiation 06/2011; 81(5):307-14. · 2.81 Impact Factor
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ABSTRACT: The mythological story of the Golden Fleece symbolizes the magical regenerative power of skin appendages. Similar to the adventurous pursuit of the Golden Fleece by the multi-talented Argonauts, today we also need an integrated multi-disciplined approach to understand the cellular and molecular processes during development, regeneration and evolution of skin appendages. To this end, we have explored several aspects of skin appendage biology that contribute to the Turing activator/inhibitor model in feather pattern formation, the topo-biological arrangement of stem cells in organ shape determination, the macro-environmental regulation of stem cells in regenerative hair waves, and potential novel molecular pathways in the morphological evolution of feathers. Here we show our current integrative biology efforts to unravel the complex cellular behavior in patterning stem cells and the control of regional specificity in skin appendages. We use feather/scale tissue recombination to demonstrate the timing control of competence and inducibility. Feathers from different body regions are used to study skin regional specificity. Bioinformatic analyses of transcriptome microarrays show the potential involvement of candidate molecular pathways. We further show Hox genes exhibit some region specific expression patterns. To visualize real time events, we applied time-lapse movies, confocal microscopy and multiphoton microscopy to analyze the morphogenesis of cultured embryonic chicken skin explants. These modern imaging technologies reveal unexpectedly complex cellular flow and organization of extracellular matrix molecules in three dimensions. While these approaches are in preliminary stages, this perspective highlights the challenges we face and new integrative tools we will use. Future work will follow these leads to develop a systems biology view and understanding in the morphogenetic principles that govern the development and regeneration of ectodermal organs.
Integrative Biology 03/2011; 3(4):388-407. · 4.51 Impact Factor
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ABSTRACT: Differences in cellular competence offer an explanation for the differences in the healing capacity of tissues of various ages and conditions. The homeobox family of genes plays key roles in governing cellular competence. Of these, we hypothesize that Msx2 is a strong candidate regulator of competence in skin wound healing because it is expressed in the skin during fetal development in the stage of scarless healing, affects postnatal digit regeneration, and is reexpressed transiently during postnatal skin wound repair. To address whether Msx2 affects cellular competence in injury repair, 3 mm full-thickness excisional wounds were created on the back of C.Cg-Msx2tm1Rilm/Mmcd (Msx2 null) mice and the healing pattern was compared with that of the wild type mice. The results show that Msx2 null mice exhibited faster wound closure with accelerated reepithelialization plus earlier appearance of keratin markers for differentiation and an increased level of smooth muscle actin and tenascin in the granulation tissue. In vitro, keratinocytes of Msx2 null mice exhibit increased cell migration and the fibroblasts show stronger collagen gel contraction. Thus, our results suggest that Msx2 regulates the cellular competence of keratinocytes and fibroblasts in skin injury repair.
Wound Repair and Regeneration 08/2009; 17(5):639 - 648. · 2.91 Impact Factor
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ABSTRACT: A key issue in stem cell biology is the differentiation of homogeneous stem cells towards different fates which are also organized into desired configurations. Little is known about the mechanisms underlying the process of periodic patterning. Feather explants offer a fundamental and testable model in which multi-potential cells are organized into hexagonally arranged primordia and the spacing between primordia. Previous work explored roles of a Turing reaction-diffusion mechanism in establishing chemical patterns. Here we show that a continuum of feather patterns, ranging from stripes to spots, can be obtained when the level of p-ERK activity is adjusted with chemical inhibitors. The patterns are dose-dependent, tissue stage-dependent, and irreversible. Analyses show that ERK activity-dependent mesenchymal cell chemotaxis is essential for converting micro-signaling centers into stable feather primordia. A mathematical model based on short-range activation, long-range inhibition, and cell chemotaxis is developed and shown to simulate observed experimental results. This generic cell behavior model can be applied to model stem cell patterning behavior at large.
Developmental Biology 08/2009; 334(2):369-82. · 4.07 Impact Factor
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ABSTRACT: A subgroup of the TNF receptor family, composed of Edar, Troy and Xedar, are implicated in the development of ectodermal appendages, such as hair follicles, teeth and sweat glands. We have isolated chicken orthologues of these three receptors and analysed their roles in early feather development. Conservation of protein sequences between mammalian and avian proteins is variable, with avian Edar showing the greatest degree of sequence identity. cXedar differs from its mammalian orthologue in that it contains an intracellular death domain. All three receptors are expressed during early feather morphogenesis and dominant negative forms of each receptor impair the epithelial contribution to feather bud morphogenesis, while the dermal contribution appears unaffected. Hyperactivation of each receptor leads to more widespread assumption of placode fate, though in different regions of the skin. Receptor signaling converges on NF-kappaB, and inhibiting this transcription factor alters feather bud number and size in a stage-specific manner. Our findings illustrate the roles of these three receptors during avian skin morphogenesis and also suggest that activators of feather placode fate undergo mutual regulation to reach a decision on skin appendage location and size.
Developmental Biology 06/2007; 305(1):232-45. · 4.07 Impact Factor
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ABSTRACT: The development and regeneration of feathers have gained much attention recently because of progress in the following areas. First, pattern formation. The exquisite spatial arrangement provides a simple model for decoding the rules of morphogenesis. Second, stem cell biology. In every molting, a few stem cells have to rebuild the entire epithelial organ, providing much to learn on how to regenerate an organ physiologically. Third, evolution and development ('Evo-Devo'). The discovery of feathered dinosaur fossils in China prompted enthusiastic inquiries about the origin and evolution of feathers. Progress has been made in elucidating feather morphogenesis in five successive phases: macro-patterning, micro-patterning, intra-bud morphogenesis, follicle morphogenesis and regenerative cycling.
Current Opinion in Cell Biology 01/2007; 18(6):730-41. · 12.90 Impact Factor
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ABSTRACT: Avian beak diversity is a classic example of morphological evolution. Recently, we showed that localized cell proliferation mediated by bone morphogenetic protein 4 (BMP4) can explain the different shapes of chicken and duck beaks (Wu et al. [2004] Science 305:1465). Here, we compare further growth activities among chicken (conical and slightly curved), duck (straight and long), and cockatiel (highly curved) developing beak primordia. We found differential growth activities among different facial prominences and within one prominence. The duck has a wider frontal nasal mass (FNM), and more sustained fibroblast growth factor 8 activity. The cockatiel has a thicker FNM that grows more vertically and a relatively reduced mandibular prominence. In each prominence the number, size, and position of localized growth zones can vary: it is positioned more rostrally in the duck and more posteriorly in the cockatiel FNM, correlating with beak curvature. BMP4 is enriched in these localized growth zones. When BMP activity is experimentally altered in all prominences, beak size was enlarged or reduced proportionally. When only specific prominences were altered, the prototypic conical shaped chicken beaks were converted into an array of beak shapes mimicking those in nature. These results suggest that the size of beaks can be modulated by the overall activity of the BMP pathway, which mediates the growth. The shape of the beaks can be fine-tuned by localized BMP activity, which mediates the range, level, and duration of locally enhanced growth. Implications of topobiology vs. molecular blueprint concepts in the Evo-Devo of avian beak forms are discussed.
Developmental Dynamics 06/2006; 235(5):1400-12. · 2.54 Impact Factor
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ABSTRACT: To accomplish regenerative medicine, several critical issues in stem cell biology have to be solved, including the identification of sources, the expanding population, building them into organs, and assimilating them to the host. Although many stem cells can now differentiate along certain lineages, knowledge on how to use them to build organs lags behind. Here we focus on topobiological events that bridge this gap, for example, the regulation of number, size, axes, shape, arrangement, and architecture during organogenesis. Rather than reviewing detail molecular pathways known to disrupt organogenesis when perturbed, we highlight conceptual questions at the topobiological level and ask how cellular and molecular mechanisms can work to explain these phenomena. The avian integument is used as the Rosetta stone because the molecular activities are linked to organ forms that are visually apparent and have functional consequences during evolution with fossil records and extant diversity. For example, we show that feather pattern formation is the equilibrium of stochastic interactions among multiple activators and inhibitors. Although morphogens and receptors are coded by the genome, the result is based on the summed physical-chemical properties on the whole cell's surface and is self-organizing. For another example, we show that developing chicken and duck beaks contain differently configured localized growth zones (LoGZs) and can modulate chicken beaks to phenocopy diverse avian beaks in nature by altering the position, number, size, and duration of LoGZs. Different organs have their unique topology and we also discuss shaping mechanisms of liver and different ways of branching morphogenesis. Multi-primordium organs (e.g., feathers, hairs, and teeth) have additional topographic specificities across the body surface, an appendage field, or within an appendage. Promises and problems in reconstitute feather/hair follicles and other organs are discussed. Finally, simple modification at the topobiological level may lead to novel morphology for natural selection at the evolution level.
Current Topics in Developmental Biology 02/2006; 72:237-74. · 6.00 Impact Factor
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ABSTRACT: The evolution of bilaterally symmetric feathers is a fundamental process leading toward flight. One major unsolved mystery is how the feathers of a single bird can form radially symmetric downy feathers and bilaterally symmetric flight feathers. In developing downy feather follicles, barb ridges are organized parallel to the long axis of the feather follicle. In developing flight-feather follicles, the barb ridges are organized helically toward the anterior region, leading to the fusion and creation of a rachis. Here we discover an anterior-posterior molecular gradient of wingless int (Wnt3)a in flight but not downy feathers. Global inhibition of the Wnt gradient transforms bilaterally symmetric feathers into radially symmetric feathers. Production of an ectopic local Wnt3a gradient reoriented barb ridges toward the source and created an ectopic rachis. We further show that the orientation of the Wnt3a gradient is dictated by the dermal papilla (DP). Swapping DPs between wing covert and breast downy feathers demonstrates that both feather symmetry and molecular gradients are in accord with the origin of the DP. Thus the fates of feather epidermal cells are not predetermined through some molecular codes but can be modulated. Together, our data suggest feathers are shaped by a DP--> Wnt gradient-->helical barb ridge organization-->creation of rachis-->bilateral symmetry sequence. We speculate diverse feather forms can be achieved by adjusting the orientation and slope of molecular gradients, which then shape the topological arrangements of feather epithelia, thus linking molecular activities to organ forms and novel functions.
Proceedings of the National Academy of Sciences 02/2006; 103(4):951-5. · 9.68 Impact Factor
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ABSTRACT: It is important to know how different organs 'manage' their stem cells. Both hair and feather follicles show robust regenerative powers that episodically renew the epithelial organ. However, the evolution of feathers (from reptiles to birds) and hairs (from reptiles to mammals) are independent events and their follicular structures result from convergent evolution. Because feathers do not have the anatomical equivalent of a hair follicle bulge, we are interested in determining where their stem cells are localized. By applying long-term label retention, transplantation and DiI tracing to map stem cell activities, here we show that feather follicles contain slow-cycling long-term label-retaining cells (LRCs), transient amplifying cells and differentiating keratinocytes. Each population, located in anatomically distinct regions, undergoes dynamic homeostasis during the feather cycle. In the growing follicle, LRCs are enriched in a 'collar bulge' niche. In the moulting follicle, LRCs shift to populate a papillar ectoderm niche near the dermal papilla. On transplantation, LRCs show multipotentiality. In a three-dimensional view, LRCs are configured as a ring that is horizontally placed in radially symmetric feathers but tilted in bilaterally symmetric feathers. The changing topology of stem cell activities may contribute to the construction of complex feather forms.
Nature 01/2006; 438(7070):1026-9. · 36.28 Impact Factor
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ABSTRACT: Beak shape is a classic example of evolutionary diversification. Beak development in chicken and duck was used to examine morphological variations among avian species. There is only one proliferative zone in the frontonasal mass of chickens, but two in ducks. These growth zones are associated with bone morphogenetic protein 4 (BMP4) activity. By "tinkering" with BMP4 in beak prominences, the shapes of the chicken beak can be modulated.
Science 10/2004; 305(5689):1465-6. · 31.20 Impact Factor
