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Feathers originate as protofeathers before birds, in pterosaurs and basal dinosaurs. What characterizes a feather is not only its outgrowth, but its barb cells differentiation and a set of beta-corneous proteins. Reticula appear concomitantly with feathers, as small bumps on plantar skin, made only of keratins. Avian scales, with their own set of beta-corneous proteins, appear more recently than feathers on the shank, and only in some species. In the chick embryo, when feather placodes form, all the non-feather areas of the integument are already specified. Among them, midventral apterium, cornea, reticula, and scale morphogenesis appear to be driven by negative regulatory mechanisms, which modulate the inherited capacity of the avian ectoderm to form feathers. Successive dermal/epidermal interactions, initiated by the Wnt/β-catenin pathway, and involving principally Eda/Edar, BMP, FGF20 and Shh signaling, are responsible for the formation not only of feather, but also of scale placodes and reticula, with notable differences in the level of Shh, and probably FGF20 expressions. This sequence is a dynamic and labile process, the turning point being the FGF20 expression by the placode. This epidermal signal endows its associated dermis with the memory to aggregate and to stimulate the morphogenesis that follows, involving even a re-initiation of the placode., Competing Interests: Declaration of competing interest The author declares no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

All living jawed vertebrates possess teeth or did so ancestrally. Integumental surface also includes the cornea. Conversely, no other anatomical feature differentiates the clades so readily as skin appendages do, multicellular glands in amphibians, hair follicle/gland complexes in mammals, feathers in birds, and the different types of scales. Tooth-like scales are characteristic of chondrichthyans, while mineralized dermal scales are characteristic of bony fishes. Corneous epidermal scales might have appeared twice, in squamates, and on feet in avian lineages, but posteriorly to feathers. In contrast to the other skin appendages, the origin of multicellular glands of amphibians has never been addressed. In the seventies, pioneering dermal-epidermal recombination between chick, mouse and lizard embryos showed that: (1) the clade type of the appendage is determined by the epidermis; (2) their morphogenesis requires two groups of dermal messages, first for primordia formation, second for appendage final architecture; (3) the early messages were conserved during amniotes evolution. Molecular biology studies that have identified the involved pathways, extending those data to teeth and dermal scales, suggest that the different vertebrate skin appendages evolved in parallel from a shared placode/dermal cells unit, present in a common toothed ancestor, c.a. 420 mya.

Feathers have long been regarded as the innovation that drove the success of birds. However, feathers have been reported from close dinosaurian relatives of birds, and now from ornithischian dinosaurs and pterosaurs, the cousins of dinosaurs. Incomplete preservation makes these reports controversial. If true, these findings shift the origin of feathers back 80 million years before the origin of birds. Gene regulatory networks show the deep homology of scales, feathers, and hairs. Hair and feathers likely evolved in the Early Triassic ancestors of mammals and birds, at a time when synapsids and archosaurs show independent evidence of higher metabolic rates (erect gait and endothermy), as part of a major resetting of terrestrial ecosystems following the devastating end-Permian mass extinction., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

While every jawed vertebrate, or its recent ancestor, possesses teeth, skin appendages are characteristic of the living clades: skin denticles (odontodes) in chondrichthyans, dermal scales in teleosts, ducted multicellular glands in amphibians, epidermal scales in squamates, feathers in birds and hair-gland complexes in mammals, all of them showing a dense periodic patterning. While the odontode origin of teleost scales is generally accepted, the origin of both feather and hair is still debated. They appear long before mammals and birds, at least in the Jurassic in mammaliaforms and in ornithodires (pterosaurs and dinosaurs), and are contemporary to scales of early squamates. Epidermal scales might have appeared several times in evolution, and basal amniotes could not have developed a scaled dry integument, as the function of hair follicle requires its association with glands. In areas such as amnion, cornea or plantar pads, the formation of feather and hair is prevented early in embryogenesis, but can be easily reverted by playing with the Wnt/BMP/Shh pathways, which both imply the plasticity and the default competence of ectoderm. Conserved ectodermal/mesenchymal signalling pathways lead to placode formation, while later the crosstalk differs, as well as the final performing tissue(s): both epidermis and dermis for teeth and odontodes, mostly dermis for teleosts scales and only epidermis for squamate scale, feather and hair. We therefore suggest that tooth, dermal scale, epidermal scale, feather and hair evolved in parallel from a shared placode/dermal cell unit, which was present in a common ancestor, an early vertebrate gnathostome with odontodes, ca. 420 million years ago., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Lingham-Soliar questions our interpretation of integumentary structures in the Middle-Late Jurassic ornithischian dinosaur Kulindadromeus as feather-like appendages and alternatively proposes that the compound structures observed around the humerus and femur of Kulindadromeus are support fibers associated with badly degraded scales. We consider this hypothesis highly unlikely because of the taphonomy and morphology of the preserved structures., (Copyright © 2014, American Association for the Advancement of Science.)

Background: The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function. Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult., Results: Recent progress in the molecular and stem cell biology of corneal morphogenesis and renewal shows that it can serves as a paradigm for epithelial /mesenchymal organ biology. This review will synthesize historical knowledge together with recent data to present a consistent overview of cornea specification, formation, maturation, and maintenance., Conclusions: This should be of interest not only to developmental biologists but also ophthalmologists, as several human vision problems are known to be rooted in defects in corneal development., (Copyright © 2014 Wiley Periodicals, Inc.)

Middle Jurassic to Early Cretaceous deposits from northeastern China have yielded varied theropod dinosaurs bearing feathers. Filamentous integumentary structures have also been described in ornithischian dinosaurs, but whether these filaments can be regarded as part of the evolutionary lineage toward feathers remains controversial. Here we describe a new basal neornithischian dinosaur from the Jurassic of Siberia with small scales around the distal hindlimb, larger imbricated scales around the tail, monofilaments around the head and the thorax, and more complex featherlike structures around the humerus, the femur, and the tibia. The discovery of these branched integumentary structures outside theropods suggests that featherlike structures coexisted with scales and were potentially widespread among the entire dinosaur clade; feathers may thus have been present in the earliest dinosaurs., (Copyright © 2014, American Association for the Advancement of Science.)

We propose a new scenario for mammary evolution based on comparative review of early mammary development among mammals. Mammary development proceeds through homologous phases across taxa, but evolutionary modifications in early development produce different final morphologies. In monotremes, the mammary placode spreads out to form a plate-like mammary bulb from which more than 100 primary sprouts descend into mesenchyme. At their distal ends, secondary sprouts develop, including pilosebaceous anlagen, resulting in a mature structure in which mammary lobules and sebaceous glands empty into the infundibula of hair follicles; these structural triads (mammolobular-pilo-sebaceous units or MPSUs) represent an ancestral condition. In marsupials a flask-like mammary bulb elongates as a sprout, but then hollows out; its secondary sprouts include hair and sebaceous anlagen (MPSUs), but the hairs are shed during nipple formation. In some eutherians (cat, horse, human) MPSUs form at the distal ends of primary sprouts; pilosebaceous components either regress or develop into mature structures. We propose that a preexisting structural triad (the apocrine-pilo-sebaceous unit) was incorporated into the evolving mammary structure, and coupled to additional developmental processes that form the mammary line, placode, bulb and primary sprout. In this scenario only mammary ductal trees and secretory tissue derive from ancestral apocrine-like glands. The mammary gland appears to have coopted signaling pathways and genes for secretory products from even earlier integumentary structures, such as odontode (tooth-like) or odontode-derived structures. We speculate that modifications in signal use (such as PTHrP and BMP4) may contribute to taxonomic differences in MPSU development.

Background: The corneal epithelium (CE) overlays a stroma, which is derived from neural crest cells, and appears to be committed during chick development, but appears still labile in adult rabbit. Its specification was hitherto regarded as resolved and dependent upon the lens, although without experimental support. Here, we challenged CE fate by changing its environment at different stages., Results: Recombination with a dermis showed that CE commitment is linked to stroma formation, which results in Pax6 stabilization in both species. Surgical ablation shows that CE specification has already taken place when the lens placode invaginates, while removal of the early lens placode led to lens renewal. To block lens formation, bone morphogenetic protein (BMP) signaling, one of its last inducing factors, was inhibited by over-expression of Gremlin in the ocular ectoderm. This resulted in lens-less embryos which formed a corneal epithelium if they survived 2 weeks., Conclusion: The corneal epithelium and lens share a common pool of precursors. The adoption of the CE fate might be dependent on the loss of a lens placode favoring environment. The corneal fate is definitively stabilized by the migration of Gremlin-expressing neural crest cells in the lens peripheral ectoderm., (Copyright © 2013 Wiley Periodicals, Inc.)

In zoology it is well known that birds are characterized by the presence of feathers, and mammals by hairs. Another common point of view is that avian scales are directly related to reptilian scales. As a skin embryologist, I have been fascinated by the problem of regionalization of skin appendages in amniotes throughout my scientific life. Here I have collected the arguments that result from classical experimental embryology, from the modern molecular biology era, and from the recent discovery of new fossils. These arguments shape my view that avian ectoderm is primarily programmed toward forming feathers, and mammalian ectoderm toward forming hairs. The other ectoderm derivatives - scales in birds, glands in mammals, or cornea in both classes - can become feathers or hairs through metaplastic process, and appear to have a negative regulatory mechanism over this basic program. How this program is altered remains, in most part, to be determined. However, it is clear that the regulation of the Wnt/beta-catenin pathway is a critical hub. The level of beta-catenin is crucial for feather and hair formation, as its down-regulation appears to be linked with the formation of avian scales in chick, and cutaneous glands in mice. Furthermore, its inhibition leads to the formation of nude skin and is required for that of corneal epithelium. Here I propose a new theory, to be further considered and tested when we have new information from genomic studies. With this theory, I suggest that the alpha-keratinized hairs from living synapsids may have evolved from the hypothetical glandular integument of the first amniotes, which may have presented similarities with common day terrestrial amphibians. Concerning feathers, they may have evolved independently of squamate scales, each originating from the hypothetical roughened beta-keratinized integument of the first sauropsids. The avian overlapping scales, which cover the feet in some bird species, may have developed later in evolution, being secondarily derived from feathers.

Feathers, like hairs, first appear as primordia consisting of an epidermal placode associated with a dermal condensation that is necessary for the continuation of their differentiation. Previously, the BMPs have been proposed to inhibit skin appendage formation. We show that the function of specific BMPs during feather development is more complex. BMP2 and BMP7, which are expressed in both the epidermis and the dermis, are involved in an antagonistic fashion in regulating the formation of dermal condensations, and thus are both necessary for subsequent feather morphogenesis. BMP7 is expressed earlier and functions as a chemoattractant that recruits cells into the condensation, whereas BMP2 is expressed later, and leads to an arrest of cell migration, likely via its modulation of the EIIIA fibronectin domain and alpha4 integrin expression. Based on the observed cell proliferation, chemotaxis and the timing of BMP2 and BMP7 expression, we propose a mathematical model, a reaction-diffusion system, which not only simulates feather patterning, but which also can account for the negative effects of excess BMP2 or BMP7 on feather formation.

During embryonic development, feathers appear first as primordia consisting of an epidermal placode associated with a dermal condensation. When 7-day chick embryo dorsal skin fragments showing three rows of feather primordia are cultured, they undergo a complete reorganization, which involves the down-regulation of morphogenetic genes and dispersal of dermal fibroblasts, leading to the disappearance of primordia. This loss of organisation is followed by de novo differentiation events. We have used this model to study potential factors involved in the formation of dermal condensations. Activation of Integrins by extracellular Manganese or intracellular Calcium prevents the initial disappearance of the dermal condensations. New primordia formation occurs even after inhibition of the Notch pathway albeit with some fusion between primordia. In conclusion, dermal fibroblast migration requires beta1-Integrin whereas the stability of dermal condensations could depend on Notch/Integrin interaction.

Differentiated cells of the corneal epithelium are converted to hair, along with their associated stem cells, then interfollicular epidermis, by means of a multistep process triggered by dermal developmental signals. The committed basal cells of the adult corneal epithelium dedifferentiate under the control of signals from an associated embryonic hair-forming dermis, likely Wnts, and revert to a limbal basal cell phenotype. This initial process involves the down-regulation of Pax6 and the loss of expression of corneal-specific keratins and the induction of basal keratinocyte markers. These dedifferentiated cells are able to reinduce dermal condensations, which in turn induce the formation of hair follicles from cells that have lost Pax6 expression, by means of a Noggin-dependent mechanism. An epidermis is subsequently formed by cells derived from the newly segregated hair stem cells.

There is increasing interest into the extent to which epithelial differentiation can be altered by mesenchymal influence, and the molecular basis for these changes. In this study, we investigated whether amnion epithelium could be transformed into skin and hair follicles by associating E12.5 to E14.5 mouse amnion from the ROSA 26 strain, with mouse embryonic hair-forming dermis from a wild-type strain. These associations were able to produce fully formed hair follicles with associated sebaceous glands, and skin epidermis. Using beta-galactosidase staining we were able to demonstrate that the follicular epithelium and skin epidermis, but not the associated dermal cells, originated from the amnion. As Noggin and Sonic hedgehog (Shh) were recently shown to be required for early chick ventral skin formation, and able to trigger skin and feather formation from chick amnion, we associated cells engineered to produce those two factors with mouse amnion. In a few cases, we obtained hair buds connected to a pluristratified epithelium; however, the transformation of the amnion was impeded by uncontrolled fibroblastic proliferation. In contrast to an earlier report, none of our control amnion specimens autonomously transformed into skin and hair follicles, indicating that specific influences are necessary to elicit follicle formation from the mouse amnion. The ability to turn amnion into skin and its appendages has practical potential for the tissue engineering of replacement skin, and related biotechnological approaches.

In the chick, most feathers are restricted to specific areas of the skin, the feather tracts or pterylae, while other areas, such as the apteria, remain bare. In the embryo, the expansion and closure of the somatopleure leads to the juxtaposition of the ventral pteryla, midventral apterium and amnion. The embryonic proximal somatopleural mesoderm is determined to form a feather-forming dermis at 2 days of incubation (E2), while the embryonic distal and the extra-embryonic somatopleure remain open to determination. We found a progressive, lateral expression of Noggin in the embryonic area, and downregulation of Msx1, a BMP4 target gene, with Msx1 expression being ultimately restricted to the most distal embryonic and extra-embryonic somatopleural mesoderm. Msx1 downregulation thus correlates with the formation of the pterylae, and its maintenance to that of the apterium. Suspecting that the inhibition of BMP4 signaling might be linked to the determination of a feather-forming dermis, we grafted Noggin-expressing cells in the distal somatopleure at E2. This elicited the formation of a supplementary pteryla in the midventral apterium. Endogenous Noggin, which is secreted by the intermediate mesoderm at E2, then by the proximal somatopleure at E4, could be sufficient to suppress BMP4 signaling in the proximal somatopleural mesoderm and then in part of the distal somatopleure, thus in turn allowing the formation of the dense dermis of the future pterylae. The same result was obtained with the graft of Shh-producing cells, but Noggin and Shh are both required in order to change the future amnion into a feather-bearing skin. A possible synergistic role of endogenous Shh from the embryonic endoderm remains to be confirmed.

The dorsal and ventral scales of the chick foot can be distinguished morphologically and molecularly: the dorsal oblong overlapping scuta expressing both alpha and beta keratins, and the ventral roundish nonprotruding reticula expressing only alpha keratins. The question arises how En-1 and Lmx1, whose role in dorsoventral limb patterning has been well established, can affect skin morphogenesis, which occurs 8 to 12 days later. Forced expression of En-1 or of Lmx1 in the hindlimb have, respectively, as expected, a ventralizing or a dorsalizing effect on skin, leading to the formation of either reticula-type or scuta-type scales on both faces. In both cases, however, the scales are abnormal and even glabrous skin without any scales at all may form. The normal inductive interactions between dermis and epidermis are disturbed after En-1 or Lmx1 misexpression. Effectively, while Lmx1 endows the dermal precursors of the ventral region with scuta inducing ability, En-1 blocks the competence of the dorsal epidermis to build scuta., (Copyright 2004 Wiley-Liss, Inc.)

Corneal epithelium transdifferentiation into a hair-bearing epidermis provides a particularly useful system for studying the possibility that transient amplifying (TA) cells are able to activate different genetic programs in response to a change in their fibroblast environment, as well as to follow the different steps of rebuilding an epidermis from induced stem cells. Corneal stem and TA cells are found in different locations - stem cells at the periphery, in the limbus, and TA cells more central. Moreover, the TA cells already express the differentiating corneal-type keratin pair K3/K12, whereas the limbal keratinocytes express the basal keratin pair K5/K14. In contrast, suprabasal epidermal keratinocytes express keratin pair K1-2/K10, and basal keratinocytes the keratin pair K5/K14. The results of tissue recombination experiments show that adult central corneal cells are able to respond to specific information originating from embryonic dermis. First, the cells located at the base of the corneal epithelium show a decrease in expression of K12 keratin, followed by an increase in K5 expression; they then proliferate and form hair follicles. The first K10 expressing cells appear at the junction of the new hair follicles and the covering corneal epithelium. Their expansion finally gives rise to epidermal strata, which displace the corneal suprabasal keratinocytes. Corneal TA cells can thus be reprogrammed to form epidermal cells, first by reverting to a basal epithelial-type, then to hair pegs and probably concomitantly to hair stem cells. This confirms the role of the hair as the main reservoir of epidermal stem cells and raises the question of the nature of the dermal messages which are both involved in hair induction and stem cell specification.

The initiation of the development of skin appendages (hair/feathers/scales) requires a signal from the competent dense dermis to the epidermis (Dhouailly, 1977). It is therefore essential to understand how to make a competent dermis. In recent years, a few studies have focused on the development of the dorsal dermis from the somitic dermomyotome. Our first aim in this review is to attempt to reconcile the available data on the origin of the dorsal dermis and summarize the present knowledge on the molecular mechanisms implicated in dermal lineage induction. Secondly, we open the discussion on the formation of a loose pre-dermal mesenchyme and more importantly of a dense dermis capable of participating in appendage development. To go further we draw a comparison between the chick and mouse systems to gain a new insight into how to initiate appendage morphogenesis and regulate the extent of hair/feather fields.

Most of the chick body is covered with feathers, while the tarsometatarsus and the dorsal face of the digits form oblong overlapping scales (scuta) and the plantar face rounded nonoverlapping scales (reticula). Feathers and scuta are made of beta-keratins, while the epidermis of reticula and inter-appendage or apteria (nude regions) express a-keratins. These regional characteristics are determined in skin precursors and require an epidermal FGF-like signal to be expressed. Both the initiation of appendages, their outline and pattern depend on signals from the dermis, while their asymmetry and outgrowth depend on epidermal competence. For example, the plantar dermis of the central foot pad induces reticula in a plantar or feathers in an apteric epidermis, in a hexagonal pattern starting from the medial point. By manipulating Shh levels in the epidermis, the regional appendage type can be changed from scuta or reticula to feather, whereas the inhibition of Wnt7a, together with a downregulation of Shh gives rise to reticula and in extreme cases, apteria. During morphogenesis of plantar skin, the epidermal expression of En-1, acting as a repressor both of Wnt7a and Shh, is linked to the formation of reticula. Finally, in birds, the complex formation of feathers, which can be easily triggered, even in the extra-embryonic somatopleure, may result from a basic genetic program, whereas the simple formation of scales appears secondarily derived, as requiring a partial (scuta) or total (reticula) inhibition of epidermal outgrowth and beta-keratin gene expression, an inhibition lost for the scuta in the case of feathered feet breeds.

This chapter is mostly a review of the pioneering work of the Philippe Sengel school in Grenoble carried out in the late sixties and the seventies. The questions raised concerning the morphogenesis of feather tracts were approached by means of microsurgery on chick embryos. P. Sengel and his wife M. Kieny had the feeling that proteins synthesized by the neural tube were required for the formation of feather fields. It was my pleasure to carry on the story from the beginning. Although some clarifications concerning this morphogenesis have been contributed by my group and by a few other laboratories interested in this subject, the most important contributions to recent research have been the elucidation of the nature of the required messages, which will be explored further in other papers in this Issue.

Skin morphogenesis occurs following a continuous series of cell-cell interactions which can be subdivided into three main stages: 1- the formation of a dense dermis and its overlying epidermis in the future appendage fields (macropattern); 2- the organization of these primary homogeneous fields into heterogeneous ones by the appearance of cutaneous appendage primordia (micropattern) and 3- cutaneous appendage organogenesis itself. In this review, we will first show, by synthesizing novel and previously published data from our laboratory, how heterogenetic and heterospecific dermal/epidermal recombinations have allowed us to distinguish between the respective roles of the dermis and the epidermis. We will then summarize what is known from the work of many different research groups about the molecular signaling which mediates these interactions in order to introduce the following articles of this Special Issue and to highlight what remains to done.

The dorsal and the ventral trunk integuments of the chick differ in their dermal cell lineage (originating from the somatic and somatopleural mesoderm respectively) and in the distribution of their feather fields. The dorsal macropattern has a large spinal pteryla surrounded by semi-apteria, whereas the ventral skin has a true medial apterium surrounded by the ventral pterylae. Comparison of the results of heterotopic transplantations of distal somatopleure in place of somatic mesoderm (Mauger 1972) or in place of proximal somatopleure (our data), leads to two conclusions. These are that the fate of the midventral apterium is not committed at day 2 of incubation and that the signals from the environment which specify the ventral and dorsal featherforming dermal progenitors are different. Effectively, Shh, but not Wnt -1 signalling can induce the formation of feather forming dermis from the embryonic somatopleure. Shh is not able, however, to trigger the formation of a feather forming dermis from the extra embryonic somatopleure. This brief report constitutes the first attempt, by comparing old and new preliminary results, to understand whether dermal progenitors at different sites are specified by different signalling pathways.

The workshop on Hair Follicle Stem Cells brought together investigators who have used a variety of approaches to try to understand the biology of follicular epithelial stem cells, and the role that these cells play in regulating the hair cycle. One of the main concepts to emerge from this workshop is that follicular epithelial stem cells are multipotent, capable of giving rise not only to all the cell types of the hair, but also to the epidermis and the sebaceous gland. Furthermore, such multipotent stem cells may represent the ultimate epidermal stem cell. Another example of epithelial stem cell and transit amplifying cell plasticity, was the demonstration that adult corneal epithelium, under the influence of embryonic skin dermis could form an epidermis as well as hair follicles. With regards to the location of follicular epithelial stem cells, immunohistochemical and ultrastructural data was presented, indicating that cells with stem cell attributes were localized to the prominent bulge region of developing human fetal hair follicles. Finally, a new notion was put forth concerning the roles that the bulge-located stem cells and the hair germ cells played with respect to the hair cycle.

The chick dorsal feather-forming dermis originates from the dorsomedial somite and its formation depends primarily on Wnt1 from the dorsal neural tube. We investigate further the origin and specification of dermal progenitors from the medial dermomyotome. This comprises two distinct domains: the dorsomedial lip and a more central region (or intervening zone) that derives from it. We confirm that Wnt1 induces Wnt11 expression in the dorsomedial lip as previously shown, and show using DiI injections that some of these cells, which continue to express Wnt11 migrate under the ectoderm, towards the midline, to form most of the dorsal dermis. Transplantation of left somites to the right side to reverse the mediolateral axis confirms this finding and moreover suggests the presence of an attractive or permissive environment produced by the midline tissues or/and a repellent or inadequate environment by the lateral tissues. By contrast, the dorsolateral dermal cells just delaminate from the surface of the intervening space, which expresses En1. Excision of the axial organs or the ectoderm, and grafting of Wnt1-secreting cells, shows that, although the two populations of dermal progenitors both requires Wnt1 for their survival, the signalling required for their specification differs. Indeed Wnt11 expression relies on dorsal neural tube-derived Wnt1, while En1 expression depends on the presence of the ectoderm. The dorsal feather-forming dermal progenitors thus appear to be differentially regulated by dorsal signals from the neural tube and the ectoderm, and derive directly and indirectly from the dorsomedial lip. As these two dermomyotomal populations are well known to also give rise to epaxial muscles, an isolated domain of the dermomyotome that contains only dermal precursors does not exist and none of the dermomyotomal domains can be considered uniquely as a dermatome.

To investigate the origin and nature of the signals responsible for specification of the dermatomal lineage, excised axial organs in 2-day-old chick embryos were replaced by grafts of the dorsal neural tube, or the ventral neural tube plus the notochord, or aggregates of cells engineered to produce Sonic hedgehog (Shh), Noggin, BMP-2, Wnt-1, or Wnt-3a. By E10, grafts of the ventral neural tube plus notochord or of cells producing Shh led to differentiation of cartilage and muscles, and an impaired dermis derived from already segmented somites. In contrast, grafts of the dorsal neural tube, or of cells producing Wnt-1, triggered the formation of a feather-inducing dermis. These results show that the dermatome inducer is produced by the dorsal neural tube. The signal can be Wnt-1 itself, or can be mediated, or at least mimicked by Wnt-1.

Hair vibrissa follicle morphogenesis involves several cell segregation phases, in the dermis as well as in the epidermis. The expression of Notch-related genes, which are well established mediators of multiple cell segregation events in Drosophila development, was studied by in situ hybridisation during embryonic mouse vibrissa follicle morphogenesis and the first adult hair cycle. The results show that two receptors, Notch1 and -2, three ligands, Delta1, Serrate1, and -2, and the three Fringe regulators, Lunatic, Manic, and Radical, are expressed in different locations and morphogenetic stages. First, the appearance of hair vibrissa primordia involves the expression of complementary patterns of Notch2, Delta1, and Lunatic Fringe in the dermis and of Notch1, Serrate2, and Lunatic Fringe in the epidermis. Second, this expression pattern is no longer found after stage 3 in the dermis. Meanwhile, in the epidermis, the expression of Notch1, Serrate2, and Lunatic Fringe before the formation of the placode may be involved in determining two populations of epidermal cells in the developing follicle. Third, complementary expression patterns for Notch1, Manic, and Lunatic Fringe, as well as Serrate1 and -2 as previously shown (Powell et al., 1998), are progressively established from stage 4 of embryonic development both in the outer root sheath and in the hair matrix. These patterns are consistent with the one found in the adult anagen phase. During the hair vibrissa cycle, Notch1 and Manic Fringe display temporal and spatial changes of expression, suggesting that they may intervene as modulators of trichocyte activities.