Enhanced Edar Signalling Has Pleiotropic Effects on Craniofacial and Cutaneous Glands

The skin carries a number of appendages, including hair follicles and a range of glands, which develop under the influence of EDAR signalling. A gain of function allele of EDAR is found at high frequency in human populations of East Asia, with genetic evidence suggesting recent positive selection at this locus. The derived EDAR allele, estimated to have reached fixation more than 10,000 years ago, causes thickening of hair fibres, but the full spectrum of phenotypic changes induced by this allele is unknown. We have examined the changes in glandular structure caused by elevation of Edar signalling in a transgenic mouse model. We find that sebaceous and Meibomian glands are enlarged and that salivary and mammary glands are more elaborately branched with increased Edar activity, while the morphology of eccrine sweat and tracheal submucosal glands appears to be unaffected. Similar changes to gland sizes and structures may occur in human populations carrying the derived East Asian EDAR allele. As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways

The Interfollicular Epidermis of Adult Mouse Tail Comprises Two Distinct Cell Lineages that Are Differentially Regulated by Wnt, Edaradd, and Lrig1

Current models of how mouse tail interfollicular epidermis (IFE) is maintained overlook the coexistence of two distinct terminal differentiation programs: parakeratotic (scale) and orthokeratotic (interscale). Lineage tracing and clonal analysis revealed that scale and interscale are maintained by unipotent cells in the underlying basal layer, with scale progenitors dividing more rapidly than interscale progenitors. Although scales are pigmented and precisely aligned with hair follicles, melanocytes and follicles were not necessary for scale differentiation. Epidermal Wnt signaling was required for scale enlargement during development and for postnatal maintenance of scale-interscale boundaries. Loss of Edaradd inhibited ventral scale formation, whereas loss of Lrig1 led to scale enlargement and fusion. In wild-type skin, Lrig1 was not expressed in IFE but was selectively upregulated in dermal fibroblasts underlying the interscale. We conclude that the different IFE differentiation compartments are maintained by distinct stem cell populations and are regulated by epidermal and dermal signals

Genome-wide SNP scan of pooled DNA reveals nonsense mutation in FGF20 in the Scaleless line of featherless chickens

<p>Abstract</p> <p>Background</p> <p>Scaleless (<it>sc/sc</it>) chickens carry a single recessive mutation that causes a lack of almost all body feathers, as well as foot scales and spurs, due to a failure of skin patterning during embryogenesis. This spontaneous mutant line, first described in the 1950s, has been used extensively to explore the tissue interactions involved in ectodermal appendage formation in embryonic skin. Moreover, the trait is potentially useful in tropical agriculture due to the ability of featherless chickens to tolerate heat, which is at present a major constraint to efficient poultry meat production in hot climates. In the interests of enhancing our understanding of feather placode development, and to provide the poultry industry with a strategy to breed heat-tolerant meat-type chickens (broilers), we mapped and identified the <it>sc</it> mutation.</p> <p>Results</p> <p>Through a cost-effective and labour-efficient SNP array mapping approach using DNA from <it>sc/sc</it> and <it>sc/+</it> blood sample pools, we map the <it>sc</it> trait to chromosome 4 and show that a nonsense mutation in <it>FGF20</it> is completely associated with the <it>sc/sc</it> phenotype. This mutation, common to all <it>sc/sc</it> individuals and absent from wild type, is predicted to lead to loss of a highly conserved region of the FGF20 protein important for FGF signalling. <it>In situ</it> hybridisation and quantitative RT-PCR studies reveal that <it>FGF20</it> is epidermally expressed during the early stages of feather placode patterning. In addition, we describe a dCAPS genotyping assay based on the mutation, developed to facilitate discrimination between wild type and <it>sc</it> alleles.</p> <p>Conclusions</p> <p>This work represents the first loss of function genetic evidence supporting a role for FGF ligand signalling in feather development, and suggests FGF20 as a novel central player in the development of vertebrate skin appendages, including hair follicles and exocrine glands. In addition, this is to our knowledge the first report describing the use of the chicken SNP array to map genes based on genotyping of DNA samples from pooled whole blood. The identification of the <it>sc</it> mutation has important implications for the future breeding of this potentially useful trait for the poultry industry, and our genotyping assay can facilitate its rapid introgression into production lines.</p

Novel Aspects in Pattern Formation Arise from Coupling Turing Reaction-Diffusion and Chemotaxis

Recent experimental studies on primary hair follicle formation and feather bud morphogenesis indicate a coupling between Turing-type diffusion driven instability and chemotactic patterning. Inspired by these findings we develop and analyse a mathematical model that couples chemotaxis to a reaction-diffusion system exhibiting diffusion-driven (Turing) instability. While both systems, reaction-diffusion systems and chemotaxis, can independently generate spatial patterns, we were interested in how the coupling impacts the stability of the system, parameter region for patterning, pattern geometry, as well as the dynamics of pattern formation. We conduct a classical linear stability analysis for different model structures, and confirm our results by numerical analysis of the system. Our results show that the coupling generally increases the robustness of the patterning process by enlarging the pattern region in the parameter space. Concerning time scale and pattern regularity, we find that an increase in the chemosensitivity can speed up the patterning process for parameters inside and outside of the Turing space, but generally reduces spatial regularity of the pattern. Interestingly, our analysis indicates that pattern formation can also occur when neither the Turing nor the chemotaxis system can independently generate pattern. On the other hand, for some parameter settings, the coupling of the two processes can extinguish the pattern formation, rather than reinforce it. These theoretical findings can be used to corroborate the biological findings on morphogenesis and guide future experimental studies. From a mathematical point of view, this work sheds a light on coupling classical pattern formation systems from the parameter space perspective

Ectodysplasin signalling deficiency in mouse models of Hypohidrotic Ectodermal Dysplasia leads to middle ear and nasal pathology

Hypohidrotic ectodermal dysplasia (HED) results from mutation of the EDA, EDAR or EDARADD genes and is characterized by reduced or absent eccrine sweat glands, hair follicles and teeth, and defective formation of salivary, mammary and craniofacial glands. Mouse models with HED also carry Eda, Edar or Edaradd mutations and have defects that map to the same structures. Patients with HED have ear, nose and throat disease, but this has not been investigated in mice bearing comparable genetic mutations. We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically dilated. Accumulation of large foreign body particles in the bulla stimulates granuloma formation. Analysis of immune cell populations and myeloid cell function shows no evidence of overt immune deficiency in HED mutant mice. Our findings using HED mutant mice as a model for the human condition support the idea that ear and nose pathology in HED patients arises as a result of nasal and nasopharyngeal gland deficits, reduced mucociliary clearance and impaired auditory tube gating function underlies the pathological sequelae in the bulla

Role of Ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia

Patients with mutations in the ectodysplasin receptor signalling pathway genes – the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD – have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa) and downless (Edardl-J/dl-J) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected heterozygous Edaraddswh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children

FGF and EDA pathways control initiation and branching of distinct subsets of developing nasal glands

Hypertrophy, hyperplasia and altered mucus secretion from the respiratory submucosal glands (SMG) are characteristics of airway diseases such as cystic fibrosis, asthma and chronic bronchitis. More commonly, hyper-secretion of the nasal SMGs contributes to allergic rhinitis and upper airway infection. Considering the role of these glands in disease states, there is a significant dearth in understanding the molecular signals that regulate SMG development and patterning. Due to the imperative role of FGF signalling during the development of other branched structures, we investigated the role of Fgf10 during initiation and branching morphogenesis of murine nasal SMGs. Fgf10 is expressed in the mesenchyme around developing SMGs while expression of its receptor Fgfr2 is seen within glandular epithelial cells. In the Fgf10 null embryo, Steno's gland and the maxillary sinus gland were completely absent while other neighbouring nasal glands showed normal duct elongation but defective branching. Interestingly, the medial nasal glands were present in Fgf10 homozygotes but missing in Fgfr2b mutants, with expression of Fgf7 specifically expressed around these developing glands, indicating that Fgf7 might compensate for loss of Fgf10 in this group of glands. Intriguingly the lateral nasal glands were only mildly affected by loss of FGF signalling, while these glands were missing in Eda mutant mice, where the Steno's and maxillary sinus gland developed as normal. This analysis reveals that regulation of nasal gland development is complex with different subsets of glands being regulated by different signalling pathways. This analysis helps shed light on the nasal gland defects observed in patients with hypohidrotic ectodermal dysplasia (HED) (defect EDA pathway) and LADD syndrome (defect FGFR2b pathway). (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Ectodysplasin signaling in cutaneous appendage development: Dose, duration and diversity

The development of several skin appendages is guided by prenatal Ectodysplasin signalling. Cui et al. (this issue, 2009) report on the dose and duration of Ectodysplasin signalling required for the maintenance and morphogenesis of different appendages. They find that achievement of an intimate arrangement between epithelial and mesenchymal cell populations correlates with the acquisition of autonomy from Ectodysplasin stimulation

Role of Ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia

Patients with mutations in the ectodysplasin receptor signalling pathway genes – the X-linked ligand ectodysplasin-A (EDA), the receptor EDAR or the receptor adapter EDARADD – have hypohidrotic ectodermal dysplasia (HED). In addition to having impaired development of teeth, hair, eccrine sweat glands, and salivary and mammary glands, HED patients have ear, nose and throat disease. The mouse strains Tabby (EdaTa) and downless (Edardl-J/dl-J) have rhinitis and otitis media due to loss of submucosal glands in the upper airway. We report that prenatal correction of EDAR signalling in EdaTa mice with the agonist anti-EDAR antibody rescues the auditory-tube submucosal glands and prevents otitis media, rhinitis and nasopharyngitis. The sparse- and wavy-haired (swh) rat strain carries a mutation in the Edaradd gene and has similar cutaneous HED phenotypes to mouse models. We report that auditory-tube submucosal glands are smaller in the homozygous mutant Edaraddswh/swh than those in unaffected heterozygous Edaraddswh/+ rats, and that this predisposes them to otitis media. Furthermore, the pathogenesis of otitis media in the rat HED model differs from that in mice, as otitis media is the primary pathology, and rhinitis is a later-onset phenotype. These findings in rodent HED models imply that hypomorphic as well as null mutations in EDAR signalling pathway genes may predispose to otitis media in humans. In addition, this work suggests that the recent successful prenatal treatment of X-linked HED (XLHED) in humans may also prevent ear, nose and throat disease, and provides diagnostic criteria that distinguish HED-associated otitis media from chronic otitis media with effusion, which is common in children