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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.)

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.)

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.

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.)

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.

Retinoic acid (RA) has marked effects on mouse upper-lip skin morphogenesis, leading to the development of glomerular gland instead of hair vibrissa follicle, but does not apparently change the dorsal pelage hair developmental program. In order to test the hypothesis that an up-regulation of the beta retinoic acid nuclear receptor (RAR beta) may be implicated in the alteration of the dermal-epidermal interactions which occur during cutaneous appendage development, RA-treated and untreated skin explants, controls as well as heterotopic recombinants, were made among nasal, upper-lip, and dorsal mouse embryonic tissues. They were analyzed by in situ hybridization with RAR beta 35S-labeled probe after 48 hr of in vitro culture as well as by identification of the morphological phenotype of cutaneous appendages after 6 additional days of culture on the chick chorioallantoic membrane. The results show that only mesenchyme from the facial region can express the RAR beta gene either normally or after RA treatment, depending on its nasal or upper-lip origin. However, the RAR beta up-regulation is unrelated to hair glandular metaplasia, which depends both on a glandular bias of the upper-lip epidermis and on the weakening of hair follicle-inducing dermal properties. The latter occurs in both the upper-lip and dorsal dermis as a consequence of RA treatment.

In order to study the determination of corneal epithelial cells, rabbit corneal epithelium of 12- to 24-day embryos, newborn and 12-day-old offspring were recombined with mouse embryo upper-lip or dorsal dermis. Epithelial differentiation was analyzed using immunohistology with corneal monospecific monoclonal antibody AK12 (anti-keratin K12). Recombinants involving 12-day embryo undifferentiated corneal ectoderm formed a typical epidermis with hair follicles after 10 days of culture on the chick chorioallantoic membrane. Central corneal epithelium from 23- to 24-day embryos and newborn, which express suprabasally both K3 and K12 keratins and basally the K12 keratin alone, when grown in association with trichogenic dermis first failed to produce K12 in its new forming basal layer and then stratified after 11 days of culture above a differentiating epidermis with hair buds. When the culture period was increased up to 21 days by grafting under the kidney capsule from athymic mice, even the central corneal epithelium of 12-day-old off-spring gave rise to a complete epidermis with emerging hairs. The vibrissal- or pelage-type of hairs was in conformity with the regional origin of the mouse dermis. The species origin of the epithelial cells of the recombinants was discriminated incontestably using the Hoechst staining of interphase nuclei. Thus, the rabbit corneal epithelial cells can transdifferentiate into epidermal keratinocytes and trichocytes at least until 12 days after birth, despite the fact that from the fifth postnatal day the cells of its basal layer express both the K3 and the K12 keratins, a keratin pair marker of corneal cell-type terminal differentiation.

Excess retinoids can cause developing mouse vibrissa follicles to be transformed into mucous glands in organ culture. The objective was to test the hypothesis that retinoids act in this system by altering morphogenetic properties of the dermis. After inititation by retinoic acid (RA) in organ culture, glands were shown to develop further in embryonic skin grafted to the chick chorioallantoic membrane (CAM). Recombinants of 12.5 day mouse epidermis with untreated or RA-treated mouse or chick dermis were then grafted to CAM for 7 days. For homospecific recombinants, 13.5 day mouse dermis originated from 11.5 day skin cultured for 2 days, with or without 5.2 microgram/ml RA. For heterospecific recombinants, 12 day dermis came from chick embryos, previously injected with 250 microgram RA. Glands were absent from the homospecific recombinants including untreated mouse dermis, but appeared in 26% of those with RA-treated dermis. Among heterospecific recombinants, 75% of those with RA-treated chick dermis and 29% of those with untreated dermis had glands. Untreated 10-12 day chick skin contained two forms of endogenous vitamin A, retinol (4.5 microgram/g protein) and dehydroretinol (3.7 microgram/g protein), while 13-14 day mouse skin contained only retinol (1.8 microgram/g protein), as shown by high performance liquid chromatography. RA injection increased retinol and dehydroretinol in chick skin, while RA was undetectable. Thus RA can act through mouse dermis to form epithelial glands and through chick dermis to increase the incidence of glands. The glands in recombinants with untreated chick dermis may result from the higher levels of endogenous retinoids in chick skin, compared with mouse skin.

The dorsal surfaces of mammalian tongues are covered with numerous projections known as filiform papillae whose morphology varies in different species. Using a panel of monoclonal antibodies to keratins as probes, we have established that, in both human and mouse, the interpapillary epithelia express mainly the "esophageal-type" keratins, while the papillary epithelia express "skin-type" keratins as well as some keratins reacting with a monoclonal antibody (AE13) to hair keratins. The AE13-reactive proteins of the mouse were found to be very similar to those of authentic mouse hair keratins. However, the corresponding protein of human tongue appears to be different from all known human keratins. This protein has a MW of 51K; it is relatively acidic; it is sulfhydryl-rich, as revealed by iodoacetic acid-induced charge and apparent size shift; it shares an epitope with all the known acidic human hair keratins; and it is associated with keratin fibrils in vivo. This protein may therefore be regarded as a novel type I "hard" keratin. These data establish that mammalian dorsal tongue epithelia can be divided into at least three compartments that undergo mainly "esophageal-", "skin-" and "hair"-types of differentiation. Different keratin filaments, e.g., those of the esophageal- and hair-types, exhibit strikingly different degrees of lateral aggregation, which can potentially account for the different physical strength and rigidity of various cellular compartments. Our data also suggest the possibility that variations in papillary structure in human and mouse may arise from different spatial arrangements of specific keratinocytes, and/or from the expression of specialized hair-related keratins.

Over the past 8 years, we have followed a child born as a harlequin baby, who survived due to treatment with retinoids. His condition evolved clinically towards the erythrodermic form of lamellar ichthyosis (non-bullous congenital ichthyosiform erythroderma. NBCIE). According to ultrastructural and biochemical criteria, our patient originally presented with type II harlequin ichthyosis. Investigations showed an abnormal keratinosome structure and extrusion, a keratin pattern characteristic for epidermal hyperproliferation, and an absence of conversion of profilaggrin to filaggrin. Persisting keratinocyte hyperproliferation, associated with the presence of a dermal infiltrate, is in agreement with the present clinical picture of severe NBCIE. However, abnormal lamellar body production and defective filaggrin processing, which is not one of the diagnostic criteria of NBCIE, persist in the patient's skin. Further studies of the epidermal lipid composition, and of possible mutations of the keratinocyte transglutaminase gene performed on epidermal cell cultures of harlequin ichthyosis, will be necessary before type II harlequin ichthyosis can be accepted as an extremely severe form of NBCIE. [ABSTRACT FROM AUTHOR]

In recent years, cutaneous epithelial stem cells have attained a genuine celebrity status. They are considered the key resource for epidermal and skin appendage regeneration, and are proposed as a preferential target of cutaneous gene therapy. Follicular epithelial stem cells may also give rise to a large variety of epithelial tumors, and cutaneous epithelial stem cells likely are crucial targets for physical or chemical agents (including carcinogens) that damage the skin and its appendages. However, as this Controversies feature illustrates, few experts can agree on how exactly to define and identify these elusive cells, or on where precisely in the skin they are localized. Given their potential importance in skin biology, pathology and future dermatological therapy, it is, therefore, timely to carefully reconsider the basic questions: What exactly is a stem cell, and how can we reliably identify epithelial stem cells? How many different kinds are there, and how do they differ functionally? Where exactly in the skin epithelium is each of the putative stem cell subpopulations located, and can we selectively manipulate any of them? [ABSTRACT FROM AUTHOR]