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The factors that determine the axial orientation and phenotypes of skin appendages were analyzed by studying the effect of retinoic acid (RA) on embryonic chicken skin explant cultures. With RA uniformly distributed in the culture media, the feather buds became smaller, were disoriented or were transformed into scale-like structures in a concentrat...
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... alone (DMSO or ethanol at the same con- centration as the experimental ones) had no effect. At low dosages (0.05 -0.75 µM) of RA, there was no effect in most (67%) of the explants (Fig. 1C), and 33% of the explants in this range of RA treatment exhibited small and short feather buds ( Fig. 1D; Table 1). With intermediate dosage (between 1 and 1.61 µM) of RA, we observed a higher frequency of small feather buds ( Fig. 1E; Table 1) and began to see many buds showing random orientations, some with axes pointed perpendicular or opposite to the normal axis ( Fig. 1F; Table 1). ...
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... low dosages (0.05 -0.75 µM) of RA, there was no effect in most (67%) of the explants (Fig. 1C), and 33% of the explants in this range of RA treatment exhibited small and short feather buds ( Fig. 1D; Table 1). With intermediate dosage (between 1 and 1.61 µM) of RA, we observed a higher frequency of small feather buds ( Fig. 1E; Table 1) and began to see many buds showing random orientations, some with axes pointed perpendicular or opposite to the normal axis ( Fig. 1F; Table 1). High RA dosage (between 2 and 2.5 µM) treatment trans- formed feather buds into skin appendages morphologically very similar to the scale ( Fig. 1G, H; Table 1). ...
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... low dosages (0.05 -0.75 µM) of RA, there was no effect in most (67%) of the explants (Fig. 1C), and 33% of the explants in this range of RA treatment exhibited small and short feather buds ( Fig. 1D; Table 1). With intermediate dosage (between 1 and 1.61 µM) of RA, we observed a higher frequency of small feather buds ( Fig. 1E; Table 1) and began to see many buds showing random orientations, some with axes pointed perpendicular or opposite to the normal axis ( Fig. 1F; Table 1). High RA dosage (between 2 and 2.5 µM) treatment trans- formed feather buds into skin appendages morphologically very similar to the scale ( Fig. 1G, H; Table 1). ...
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... intermediate dosage (between 1 and 1.61 µM) of RA, we observed a higher frequency of small feather buds ( Fig. 1E; Table 1) and began to see many buds showing random orientations, some with axes pointed perpendicular or opposite to the normal axis ( Fig. 1F; Table 1). High RA dosage (between 2 and 2.5 µM) treatment trans- formed feather buds into skin appendages morphologically very similar to the scale ( Fig. 1G, H; Table 1). This similarity can be appreciated by comparing Fig. 1E and 8C′, whole- mount and longitudinal sections of RA-converted feather buds, with reticulate scales shown in Fig. 2b and 1d of Zelitinger and Sawyer (1992). ...
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... have earlier shown that the chicken protein or proteins which immuno-cross reacted with antibodies to XlHbox 1 (desig- †Number of total beads implanted. ‡In these experiments, it was difficult to differentiate the slow growth and scale-like buds as listed in Table 1. They were pooled in this "small and round buds" category. ...
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... et al. (1990) have hypothesized that morphogenesis of skin appendages can be divided into at least two stages: an induc- tion stage during which the decision to initiate a skin appendage is made, followed by a specification stage during which the specific phenotype of the skin appendage is deter- mined. In our experiment, we observed the largest spectrum of converted phenotypes when RA was added at a time after small dermal condensations had already formed (stage 33- 34, Table 1). If RA was added earlier than stage 31 at the time dermal condensations were just forming, most skin appendages were completely inhibited and a flat explant was obtained. ...
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Citations
... Another method involves grafting embryonic explants on a chorioallantoic membrane [184]. When embryonic chicken skin explants are cultivated, feather buds can develop [184,187]. One drawback is the limited time (about 5 days) the skin explant structure and integrity can be maintained in culture. ...
This article reviews the avian viruses that infect the skin of domestic farm birds of primary economic importance: chicken, duck, turkey, and goose. Many avian viruses (e.g., poxviruses, herpesviruses, Influenza viruses, retroviruses) leading to pathologies infect the skin and the appendages of these birds. Some of these viruses (e.g., Marek’s disease virus, avian influenza viruses) have had and/or still have a devasting impact on the poultry economy. The skin tropism of these viruses is key to the pathology and virus life cycle, in particular for virus entry, shedding, and/or transmission. In addition, for some emergent arboviruses, such as flaviviruses, the skin is often the entry gate of the virus after mosquito bites, whether or not the host develops symptoms (e.g., West Nile virus). Various avian skin models, from primary cells to three-dimensional models, are currently available to better understand virus-skin interactions (such as replication, pathogenesis, cell response, and co-infection). These models may be key to finding solutions to prevent or halt viral infection in poultry.
... While the mechanism underlying global feather orientation is not understood, A-P polarity in the adult follicle, controlled by a Wnt 3a gradient, determines the position of the rachis, the major backbone of the feather (Yue et al., 2006). The A-P axis is also influenced by retinoic acid (Chuong et al., 1992) and Wnt 7a (Widelitz et al., 2000) gradients which lead to polarized Notch-Delta pathway expression (Chen et al., 1997). We also employed a tissue transplantation strategy used to identify polarization activity in the limb bud (Saunders, 1972) to identify a zone of "feather polarizing activity", positioned in the posterior feather bud mesenchyme (Li et al., 2013). ...
... In situ hybridization and immunohistochemistry Skin and embryos were fixed in 4% paraformaldehyde and processed for RNA whole mount in situ hybridization or immunohistochemistry (Jiang and Chuong, 1992;Ting-Berreth and Chuong, 1996) . An antisense RNA probe was prepared for in situ hybridization. ...
During chicken skin development, each feather bud exhibits its own polarity, but a population of buds organize with a collective global orientation. We used embryonic dorsal skin, with buds aligned parallel to the rostral-caudal body axis, to explore whether exogenous electric fields affect feather polarity. Interestingly, brief exogenous current exposure prior to visible bud formation later altered bud orientations. Applying electric pulses perpendicular to the body rostral-caudal axis realigned bud growth in a collective swirl resembling an electric field pointing toward the anode. Perturbed buds show normal molecular expression and morphogenesis except for their altered orientation. Epithelial-mesenchymal recombination demonstrates the effects of exogenous electric fields are mediated through the epithelium. Small molecule channel inhibitor screens show Ca²⁺ channels and PI3 Kinase are involved in controlling feather bud polarity. This work reveals the importance of bioelectricity in organ development and regeneration and provides an explant culture platform for experimentation.
... In addition, one of the DEKGs named ACER1 (alkaline ceramidase 1) also mediated the growth arrest and differentiation of keratinocytes (Mao and Obeid, 2008). Retinoic acid has an effect on the feather formation and axial orientation of skin appendages (Chuong et al., 1992;Chuong, 1993). In the present study, several GO terms (GO: 0005501, GO: 0034653, and GO: 0048387) related to retinoic acid were enriched, which implies that some genes of the biochemical processes of retinoic acid may play a role in the formation of the feather rate phenotype. ...
The feather rate phenotype in chicks, including early-feathering and late-feathering phenotypes, are widely used as a sexing system in the poultry industry. The objective of this study was to obtain candidate genes associated with the feather rate in Shouguang chickens. In the present study, we collected 56 blood samples and 12 hair follicle samples of flight feathers from female Shouguang chickens. Then we identified the chromosome region associated with the feather rate by genome-wide association analysis (GWAS). We also performed RNA sequencing and analyzed differentially expressed genes between the early-feathering and late-feathering phenotypes using HISAT2, StringTie, and DESeq2. We identified a genomic region of 10.0–13.0 Mb of chromosome Z, which is statistically associated with the feather rate of Shouguang chickens at one-day old. After RNA sequencing analysis, 342 differentially expressed known genes between the early-feathering (EF) and late-feathering (LF) phenotypes were screened out, which were involved in epithelial cell differentiation, intermediate filament organization, protein serine kinase activity, peptidyl-serine phosphorylation, retinoic acid binding, and so on. The sperm flagellar 2 gene (SPEF2) and prolactin receptor (PRLR) gene were the only two overlapping genes between the results of GWAS and differential expression analysis, which implies that SPEF2 and PRLR are possible candidate genes for the formation of the chicken feathering phenotype in the present study. Our findings help to elucidate the molecular mechanism of the feather rate in chicks.
... E3 chicken embryos were transduced with RCAS-β-catenin [9]. E9 chicken embryos were treated with all-trans retinoic acid (RA, Tretinoin) [23]. RCAS-GFP treated samples was used as the control. ...
Background
The molecular mechanism controlling regional specific skin appendage phenotypes is a fundamental question that remains unresolved. We recently identified feather and scale primordium associated genes and with functional studies, proposed five major modules are involved in scale-to-feather conversion and their integration is essential to form today’s feathers. Yet, how the molecular networks are wired and integrated at the genomic level is still unknown.
Results
Here, we combine classical recombination experiments and systems biology technology to explore the molecular mechanism controlling cell fate specification. In the chimeric explant, dermal fate is more stable, while epidermal fate is reprogrammed to be similar to the original appendage type of the mesenchyme. We analyze transcriptome changes in both scale-to-feather and feather-to-scale transition in the epidermis. We found a highly interconnected regulatory gene network controlling skin appendage types. These gene networks are organized around two molecular hubs, β-catenin and retinoic acid (RA), which can bind to regulatory elements controlling downstream gene expression, leading to scale or feather fates. ATAC sequencing analyses revealed about 1000 altered widely distributed chromatin open sites. We find that perturbation of a key gene alters the expression of many other co-expressed genes in the same module.
Conclusions
Our findings suggest that these feather / scale fate specification genes form an interconnected network and rewiring of the gene network can lead to changes of appendage phenotypes, acting similarly to endogenous reprogramming at the tissue level. This work shows that key hub molecules, β-catenin and retinoic acid, regulate scale / feather fate specification gene networks, opening up new possibilities to understand the switches controlling organ phenotypes in a two component (epithelial and mesenchyme) system.
... Liver explants were prepared in a manner similar to that reported elsewhere for skin culture [10]. Briefly, the liver tissue was dissected in Hank's buffered saline solution (Gibco/BRL) under a dissection microscope and placed on culture inserts in six-well culture dishes (Falcon). ...
Because the molecular mechanisms of morphogenesis of the hepatic cord and sinus are unclear, we investigated the involvement of bone morphogenetic protein (BMP4) in hepatic sinusoid morphogenesis.
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Our results show that proper BMP signaling mediates peri-sinusoidal cell-hepatoblast interactions during development; this is essential for hepatic cord organization among hepatoblasts, endothelium, and presumptive hepatic stellate cells.
... Retinoic acid (RA) synthesizing pathway is important to avian epidermal development (Chuong et al., 1992;Dhouailly et al., 1980;Fisher et al., 1988). Application of RA in chicken during early embryogenesis (~day 7-10) was shown to induce feather fated skin explants to form scale like structures and reticulate scale epithelium to form feather like structures that express feather specific genes (Chuong et al., 1992;Dhouailly et al., 1980;Fisher et al., 1988). ...
... Retinoic acid (RA) synthesizing pathway is important to avian epidermal development (Chuong et al., 1992;Dhouailly et al., 1980;Fisher et al., 1988). Application of RA in chicken during early embryogenesis (~day 7-10) was shown to induce feather fated skin explants to form scale like structures and reticulate scale epithelium to form feather like structures that express feather specific genes (Chuong et al., 1992;Dhouailly et al., 1980;Fisher et al., 1988). Retinoic acid is synthesized from retinol (vitamin A) by two oxidative steps using alcohol dehydrogenases to produce retinaldehyde which is then oxidized into retinoic acid by retinaldehyde dehydrogenases (RALDH1, 2 and 3; now referred to as ALDH1A1, ALDH1A2, and ALDH1A3; Niederreither et al., 2002). ...
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Previous studies have shown that miRNA regulation contributes to a diverse set of processes including cellular differentiation and morphogenesis which leads to the creation of different cell types in multicellular organisms and is thus key to animal development. Feathers are one of the most distinctive features of extant birds and are important for multiple functions including flight, thermal regulation, and sexual selection. However, the role of miRNAs in feather development has been woefully understudied despite the identification of cell signaling pathways, cell adhesion molecules and structural genes involved in feather development. In this study, we performed a microarray experiment comparing the expression of miRNAs and mRNAs among three embryonic stages of development and two tissues (scutate scale and feather) of the chicken. We combined this expression data with miRNA target prediction tools and a curated list of feather related genes to produce a set of 19 miRNA-mRNA duplexes. These targeted mRNAs have been previously identified as important cell signaling and cell adhesion genes as well as structural genes involved in feather and scale morphogenesis. Interestingly, the miRNA target site of the cell signaling pathway gene, Aldehyde Dehydrogenase 1 Family, Member A3 (ALDH1A3), is unique to birds indicating a novel role in Aves. The identified miRNA target site of the cell adhesion gene, Tenascin C (TNC), is only found in specific chicken TNC splice variants that are differentially expressed in developing scutate scale and feather tissue indicating an important role of miRNA regulation in epidermal differentiation. Additionally, we found that β-keratins, a major structural component of avian and reptilian epidermal appendages, are targeted by multiple miRNA genes. In conclusion, our work provides quantitative expression data on miRNAs and mRNAs during feather and scale development and has produced a highly diverse, but manageable list of miRNA-mRNA duplexes for future validation experiments.
... An amount of 16.7 μm of ATRA induces glandular metaplasia in mouse embryonic upper-lip skin instead of hair vibrissa follicle [12,13]. Many of the abnormalities in pattern formation and organ formation that result from the addition of exogenous RA during embryogenesis are related in part to the ability of retinoids to change the pattern of expression of the clusters of homeobox genes in the embryo [14][15][16][17]. Many homeobox genes have been shown to change their expression in the skin as a response to RA [18][19][20]. ...
... RA is known to regulate cell proliferation, differentiation, and morphogenesis during the normal development of many tissues [16,28]. Two cutaneous structures of chick, i.e., scales and feathers, have been studied extensively to define the mechanism of retinoid-induced morphogenetic change [11,14,15,20,[29][30][31]. Dhouailly et al. (1980) showed that the single injection of 125 μg (417 μm) of ATRA into the amniotic cavity of chick embryos at embryonic Hamburger-Hamilton (HH) stage 36 (day 10), which correspond to the beginning of scale morphogenesis, leads to the formation of feathers on chick foot scales [29]. ...
... Two cutaneous structures of chick, i.e., scales and feathers, have been studied extensively to define the mechanism of retinoid-induced morphogenetic change [11,14,15,20,[29][30][31]. Dhouailly et al. (1980) showed that the single injection of 125 μg (417 μm) of ATRA into the amniotic cavity of chick embryos at embryonic Hamburger-Hamilton (HH) stage 36 (day 10), which correspond to the beginning of scale morphogenesis, leads to the formation of feathers on chick foot scales [29]. An amount of 2.5 μm of RA also modulates axis orientation and phenotypes of skin appendages [14]. Using chick embryonic skin cultured in vitro, we examined the mechanism of the mucous transdifferentiation induced by RA and showed that in chick embryonic tarsometatarsal skin, this transdifferentiation to a mucous epithelium is induced by the interaction of the epidermis with the dermis, when dermal fibroblasts are pretreated with retinol ( Figure 1) [21,[32][33][34][35]. Furthermore, 1 μm ATRA inhibits feather bud formation and induces the transdifferentiation of the epidermis of chick embryonic dorsal skin to a mucous one [36]. ...
Retinoids function as important regulatory signaling molecules during development, acting in cellular growth and differentiation both during embryogenesis and in the adult animal. In 1953, Fell and Mellanby first found that excess vitamin A can induce transdifferentiation of chick embryonic epidermis to a mucous epithelium (Fell, H.B.; Mellanby, E. Metaplasia produced in cultures of chick ectoderm by high vitamin A. J. Physiol. 1953, 119, 470–488). However, the molecular mechanism of this transdifferentiation process was unknown for a long time. Recent studies demonstrated that Gbx1, a divergent homeobox gene, is one of the target genes of all-trans retinoic acid (ATRA) for this transdifferentiation. Furthermore, it was found that ATRA can induce the epidermal transdifferentiation into a mucosal epithelium in mammalian embryonic skin, as well as in chick embryonic skin. In the mammalian embryonic skin, the co-expression of Tgm2 and Gbx1 in the epidermis and an increase in TGF-β2 expression elicited by ATRA in the dermis are required for the mucosal transdifferentiation, which occurs through epithelial-mesenchymal interaction. Not only does retinoic acid (RA) play an important role in mucosal transdifferentiation, periderm desquamation, and barrier formation in the developing mammalian skin, but it is also involved in hair follicle downgrowth and bending by its effect on the Wnt/β-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families.
... At E17.5 and E18.5, Cyp26b12/2 mice have reduced thickness of the cornified layer of skin, reduced filaggrin and arrest of hair follicle growth (32). Interestingly, experiments using RA-soaked beads in embryonic chicken skin explant cultures also showed that the beads can create a radial zone of inhibition surrounded by a rim of disoriented buds (33). Skin equivalents treated with RA in vitro show altered epidermal stratification (34), and keratinocyte cultures treated with RA show increased sensitivity to apoptosis with upregulated p53 and caspase-3, -6, -7 and -9 (35). ...
Focal facial dermal dysplasia (FFDD) Type IV is a rare syndrome characterized by facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. To identify the causative gene(s), exome sequencing was performed in a family with two affected sibs. Assuming autosomal recessive inheritance, two novel sequence variants were identified in both sibs in CYP26C1 - a duplication of 7 basepairs that was maternally inherited, c.844_851dupCCATGCA, predicting p.Glu284fsX128, and a missense mutation, c.1433G>A, predicting p.Arg478His, that was paternally inherited. The duplication predicted a frameshift mutation that lead to a premature stop codon and premature chain termination, while the missense mutation was not functional based on its in-vitro expression in mammalian cells. The FFDD skin lesions arise along the sites of fusion of the maxillary and mandibular prominences early in facial development and Cyp26c1 was expressed exactly along the fusion line for these facial prominences in the first branchial arch in mice. Sequencing of four additional, unrelated Type IV FFDD patients and eight Type II or III TWIST2-negative FFDD patients revealed that three of the Type IV patients were homozygous for the duplication, whereas none of the Type II or III patients had CYP26C1 mutations. The 7 basepair duplication was present in 0.3% of healthy controls and 0.3% of patients with other birth defects. These findings suggest that the phenotypic manifestations of FFDD Type IV can be non-penetrant or under-ascertained. Thus, FFDD Type IV results from loss of function mutations in CYP26C1.
... These receptors mediate ligand-dependent target gene transcription, typically by binding as heterodimers to cis-acting retinoic acid response elements (Chambon, 1996). Many of the abnormalities in pattern formation and organ formation that result from the exogenous addition of retinoic acid during embryogenesis are related in part to the ability of retinoids to change the pattern of expression of the clusters of homeobox (Hox) genes in the embryo (Chuong et al., 1992;Cardoso et al., 1996). Fell and Mellanby (1953) first found that excess vitamin A can induce transdifferentiation of chick embryonic epidermis to a mucous epithelium. ...
... Modulation of the axis orientation by treatment with 1 mM retinoic acid throughout the culture period results in a higher frequency of small feather buds and many buds showing random orientations (Chuong et al., 1992). However, in the present study 1 mM retinoic acid was used for treatment for only 1 day, along with 10 nM hydrocortisone, and the skin was cultured for an additional 4 days without these chemicals, and a different result was obtained. ...
Retinoic acid, an active metabolite of retinol, is known to regulate cell proliferation, differentiation, and morphogenesis during normal development of many tissues. Using chick embryonic tarsometatarsal skin, we showed previously that the expression of Gbx1, a divergent homeobox gene, is increased in the epidermis through interaction with retinol-pretreated dermal fibroblasts followed by epidermal transdifferentiation to mucous epithelium. This present study was performed to elucidate the effects of retinoic acid and Gbx1 on feather-bud formation and epidermal transdifferentiation.
We showed that Gbx1 was expressed in the chick embryonic dorsal epidermis as early as at placode stage (Hamburger and Hamilton stage 31) and increased in amount during feather-bud formation. Treatment with 1 μM retinoic acid for 24 hr inhibited feather-bud formation and induced the transdifferentiation of the epidermis to a mucosal epithelium with a concomitant increase in Gbx1 mRNA expression in the epithelium. Furthermore, transient transfection of the epidermis with Gbx1 cDNA by electroporation induced elongation of the feather bud, but did not result in transdifferentiation.
These results indicate that Gbx1 was involved in the feather-bud formation and was one of target genes of retinoic acid and that other signals in addition to Gbx1 were required for epidermal mucous transdifferentiation.
... Retinoic acid is a hormetic morphogen that like TGF-β causes apoptosis at very high concentrations. Retinoic acid diffusing from pellets soaked in retinoic acid and placed on cultured explants of embryonic chicken skin can cause apoptosis of adjacent cells and form rings of cell disintegration and complete lack of cell growth around the pellets; the diameter of the cleared area increases with increasing concentration of the morphogen in the pellet (Chuong et al. 1992). Based upon findings by the Chuong group on the effects of retinoid acid and on the reported in vitro hormetic responses to TGF-β noted above (Battegay et al. 1990;Qiu 1995;Fosslien et al. 1997), it seems reasonable to generalize that a hormetic morphogen diffusing from a central pellet would form three circles around the pellet, a central circle of apoptosis surrounded by a ring of growth inhibition followed by a ring of growth stimulation ( Figure 2, top panel). ...
... I have proposed that radial transmural ATP gradients can induce transmural ionic currents and transmural electrical fields that play a role in the development of the typical coaxial arrangement of vascular mural cells (Fosslien 2010). Involvement of electrical fields in vessel wall development is supported by reports that electrical fields can induce curvature of cells (Rajnicek et al. 1994), align elongated cells perpendicular to the fields (Chuong et al. 1992), and modulate bidirectional cell migration (Sato et al. 2009). A vital role for electrical fields in curvature formation in plants has been demonstrated as well: Schrank (1950) found that shunting of inherent electrical fields using an electrolyte completely abolished curvature responses of Avena sativa coleoptiles. ...
Hormetic morphogens are morphogens such as transforming growth factor beta (TGF-β) in mammals and auxin in plants that induce hormetic responses. For example, in vitro, TGF-β stimulates and inhibits cell proliferation at low and high concentrations respectively. I developed a model of hormetic morphogen gradient control of the morphogenesis of the fusion of bilateral aortic precursors (Anlagen) that form the aorta during development; and validated the model with findings obtained by Daucus Carota fusion experiments. Theoretically, radial concentration gradients of a hormetic morphogen can form hollow (vessels) or solid (Carota) tubular structures. In arteries, blood flow and pressure can shape mural gradients and determine wall curvature and thereby vessel diameter. As Anlagen grow they form a temporary common wall that is subsequently removed, which results in fusion of the Anlagen lumina and an aorta with a lumen diameter that accommodates the combined blood flow to the iliac arteries. Carota seedlings grown close together exhibited proximally fused root cones, serial cross-sections of which exhibited coaxial fusion patterns that closely resembled the predicted vascular fusion patterns, thus validating a role for hormesis and hormetic morphogens in the morphogenesis of the aorta and possibly the morphogenesis of other human midline structures.
