RESUMEN
A growing body of evidence emerging supported that ectodysplasin-A (EDA) signaling pathway contributed to craniofacial development. However, their expression in condyle has not been elucidated yet. This study investigated the expression patterns of EDA, EDA receptor (EDAR), and EDAR-associated death domain (EDARADD) in condyle of postnatal mice. Histological staining and micro-computed tomography (CT) scanning showed that as endochondral ossification proceeded, the thickness of chondrocyte layer decreased, and the volume of mandibular condyle increased. Osteoclasts remained active throughout the condylar development. Immunohistochemistry staining demonstrated that EDA was expressed in almost all layers during the first 2 weeks after birth. EDA shifted from the mature and hypertrophic layers to fibrous and proliferating layers at postnatal 3 weeks. As condyle matured, the distribution of EDA tended to be limited to hypertrophic layer. The distribution patterns of EDAR and EDARADD were consistent with EDA, while the level of EDAR expression was slightly lower. mRNA expression levels of EDA signaling pathway-related components increased after birth. Furthermore, we evaluated the expression of EDA using ATDC5 in vitro. EDA increased during the late stage of chondrogenesis. These findings proved that EDA signaling pathway was involved in condylar development and acted as a regulatory factor in condylar maturation and differentiation.
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Ectodisplasinas , Cóndilo Mandibular , Ratones , Animales , Ectodisplasinas/metabolismo , Cóndilo Mandibular/metabolismo , Microtomografía por Rayos X , Transducción de Señal , Receptores de la Ectodisplasina/metabolismoRESUMEN
EDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X-linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.
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Displasia Ectodermal Anhidrótica Tipo 1 , Displasia Ectodérmica , Humanos , Ratones , Animales , Displasia Ectodermal Anhidrótica Tipo 1/genética , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Displasia Ectodérmica/genética , Transducción de Señal , Ectodermo/metabolismo , Mutación , Receptor Edar/genéticaRESUMEN
XEDAR is a member of the TNF receptor subfamily and a mediator of the ectodysplasin (EDA) pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class, which includes hair, eccrine sweat glands, and mammary glands. Loss-of-function sequence variants of EDA, which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia characterized by defects in two or more types of ectodermal appendages. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. Although the contributions of the EDA-A1/EDAR signaling pathway to EDA-dependent ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. In this study, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouse Xedar knockout model, we show that Xedar has a specific and temporally restricted role in promoting late pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings implicate Xedar in ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology of EDA-dependent mammary phenotypes.
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Ectodisplasinas , Proteínas de la Membrana , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Proteínas de la Membrana/genética , Morfogénesis , Receptores del Factor de Necrosis Tumoral , Transducción de Señal , Animales , RatonesRESUMEN
Ectodysplasin A (EDA) signaling is initially identified as morphogenic signaling regulating the formation of skin appendages including teeth, hair follicles, exocrine glands in mammals, feathers in birds and scales in fish. Gene mutation in EDA signaling causes hypohidrotic ectodermal dysplasia (HED), a congenital hereditary disease with malformation of skin appendages. Interestingly, emerging evidence suggests that EDA and its receptors can modulate the proliferation, apoptosis, differentiation and migration of cancer cells, and thus may regulate tumorigenesis and cancer progression. More recently, as a newly discovered hepatocyte factor, EDA pathway has been demonstrated to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and type II diabetes by regulating glucose and lipid metabolism. In this review, we summarize the function of EDA signaling from skin appendage development to multiple other diseases, and discuss the clinical application of recombinant EDA protein as well as other potential targets for disease intervention.
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Diabetes Mellitus Tipo 2 , Displasia Ectodermal Anhidrótica Tipo 1 , Animales , Diabetes Mellitus Tipo 2/metabolismo , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Mamíferos/metabolismo , Transducción de Señal , Piel/metabolismoRESUMEN
INTRODUCTION: The interaction between activated hepatic stellate cells (aHSCs) and macrophages is central to liver fibrosis development. The cargo contained within aHSC exosomes (aHSC-EXOs) and how aHSC-EXOs affect macrophage function is poorly understood. METHODS: RNA from aHSC-EXOs was separated into small (<200-basepairs) and large (≥200-basepairs) RNA species, transfected into macrophages, and macrophage IL-6 and TNFα mRNA expression and protein secretion measured. Next generation sequencing was performed on EXOs from rat quiescent and aHSCs and human aHSCs. aHSCs were transfected with siRNA against ectodysplasin-A (EDA), EXOs collected, and their effect on macrophage function analyzed. Human cirrhotic liver was analyzed for EDA mRNA expression and compared to non-tumor liver (NTL). RESULTS: Transfection with large RNA from aHSC-EXOs stimulated macrophage IL-6 and TNFα mRNA expression and protein secretion. EDA mRNA was highly expressed in aHSCs and transfection of aHSCs with EDA-siRNA decreased aHSC-EXO EDA mRNA and blunted the effect of aHSC-EXOs on macrophage function (IL-6/TNFα expression and macrophage migration). Human cirrhotic liver exhibited high EDA mRNA compared to NTL. CONCLUSIONS: HSC activation leads to altered EXO mRNA/miRNA profiles with aHSC-EXOs mRNAs exerting a dominant role in altering macrophage function. Ectodysplasin-A mRNA is an important component in aHSC-EXOs in regulating macrophage function.
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Exosomas , Neoplasias Hepáticas , Animales , Ectodisplasinas/metabolismo , Ectodisplasinas/farmacología , Receptor Edar , Exosomas/metabolismo , Células Estrelladas Hepáticas/metabolismo , Humanos , Interleucina-6/metabolismo , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Macrófagos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To discover novel ectodysplasin-A (EDA) and wingless-type MMTV integration site family, member 10A (WNT10A) mutations in tooth agenesis (TA) patients. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Guanghua School of Stomatology, Guangzhou, China, from March 2018 to August 2020. METHODOLOGY: EDA and WNT10A were analysed in eleven TA families by PCR and Sanger sequencing. Bioinformatics and structure modelling analyses were performed after identifying different variants, to predict the resulting conformational alterations in WNT10A and EDA. RESULTS: Two novel mutations (c.796C>A (p.L266I), c.769G>A (p.G257R)) in EDA and two reported mutations (c.637G>A (p.G213S), c.511C>T (p.R171C))in WNT 10A were detected. Combined with the 3D structural analysis, we discovered a correlation between alterations in hydrogen bond formation and the observed phenotypes, potentially affecting protein binding. CONCLUSIONS: The mutations were predicted to be pathogenic through bioinformatics analyses. In addition, by identifying novel mutations, our knowledge regarding the TA spectrum and tooth development was considerably expanded. KEY WORDS: Anodontia, EDA, WNT 10A, Whole exome sequencing, Odontogenesis.
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Anodoncia , Ectodisplasinas , Anodoncia/genética , Ectodisplasinas/química , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Humanos , Mutación , Linaje , Fenotipo , Secuenciación del ExomaRESUMEN
X-linked hypohidrotic dysplasia (XLHED), caused by mutations in the EDA gene, is a rare genetic disease that affects the development and function of the teeth, hair, nails, and sweat glands. The structural and functional consequences of caused by an ectodysplasin-A (EDA) mutations on protein phenotype, stability, and posttranslational modifications (PTMs) have not been well investigated. The present investigation involves five missense mutations that cause XLHED (L56P, R155C, P220L, V251M, and V322A) in different domains of EDA (TM, furin, collagen, and tumor necrosis factor [TNF]) from previously published papers. The deleterious nature of EDA mutant variants was identified using several computational algorithm tools. The point mutations induce major drifts in the structural flexibility of EDA mutant variants and have a negative impact on their stability, according to the 3D protein modeling tool assay. Using the molecular docking technique, EDA/EDA variants were docked to 10 EDA interacting partners, retrieved from the STRING database. We found a novel biomarker CD68 by molecular docking analysis, suggesting all five EDA variants had lower affinity for EDAR, EDA2R, and CD68, implying that they would affect embryonic signaling between the ectodermal and mesodermal cell layers. In silico research such as gene ontology, subcellular localization, protein-protein interaction, and PTMs investigations indicates major functional alterations would occur in EDA variants. According to molecular simulations, EDA variants influence the structural conformation, compactness, stiffness, and function of the EDA protein. Further studies on cell line and animal models might be useful in determining their specific roles in functional annotations.
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Biología Computacional , Displasia Ectodermal Anhidrótica Tipo 1/genética , Ectodisplasinas/química , Ectodisplasinas/genética , Simulación del Acoplamiento Molecular , Mutación Missense , Sustitución de Aminoácidos , Displasia Ectodermal Anhidrótica Tipo 1/metabolismo , Ectodisplasinas/metabolismo , Humanos , Relación Estructura-ActividadRESUMEN
Previous studies have shown that microRNAs (miRNAs) are closely related to many viral infections. However, the molecular mechanism of how miRNAs regulate porcine epidemic diarrhea virus (PEDV) infection remains unclear. In this study, we first constructed a PEDV-infected IPEC-J2 cytopathic model to validate the relationship between miR-129a-3p expression levels and PEDV resistance. Secondly, we explored the effect of miR-129a-3p on PEDV infection by targeting the 3'UTR region of the ligand ectodysplasin (EDA) gene. Finally, transcriptome sequencing was used to analyze the downstream regulatory mechanism of EDA. The results showed that after 48 h of PEDV infection, IPEC-J2 cells showed obvious pathological changes, and miR-129a-3p expression was significantly downregulated (p < 0.01). Overexpression of miR-129a-3p mimics inhibited PEDV replication in IPEC-J2 cells; silencing endogenous miR-129a-3p can promote viral replication. A dual luciferase assay showed that miR-129a-3p could bind to the 3'UTR region of the EDA gene, which significantly reduced the expression level of EDA (p < 0.01). Functional verification showed that upregulation of EDA gene expression significantly promoted PEDV replication in IPEC-J2 cells. Overexpression of miR-129a-3p can activate the caspase activation and recruitment domain 11 (CARD11) mediated NF-κB pathway, thus inhibiting PEDV replication. The above results suggest that miR-129a-3p inhibits PEDV replication in IPEC-J2 cells by activating the NF-κB pathway by binding to the EDA 3'UTR region. Our results have laid the foundation for in-depth study of the mechanism of miR-129a-3p resistance and its application in porcine epidemic diarrhea disease-resistance breeding.
Asunto(s)
Infecciones por Coronavirus/metabolismo , Ectodisplasinas/metabolismo , Enterocitos/metabolismo , MicroARNs/metabolismo , FN-kappa B/metabolismo , Virus de la Diarrea Epidémica Porcina/fisiología , Transducción de Señal/genética , Replicación Viral/genética , Regiones no Traducidas 3' , Animales , Chlorocebus aethiops , Infecciones por Coronavirus/virología , Regulación hacia Abajo/genética , Ectodisplasinas/genética , Enterocitos/virología , Células HEK293 , Humanos , MicroARNs/genética , Porcinos , Transfección , Regulación hacia Arriba/genética , Células Vero , Secuenciación del Exoma/métodosRESUMEN
Ectodysplasin A (EDA) was recently identified as a liver-secreted protein that is increased in the liver and plasma of obese mice and causes skeletal muscle insulin resistance. We assessed if liver and plasma EDA is associated with worsening non-alcoholic fatty liver disease (NAFLD) in obese patients and evaluated plasma EDA as a biomarker for NAFLD. Using a cross-sectional study in a public hospital, patients with a body mass index >30 kg/m2 (n=152) underwent liver biopsy for histopathology assessment and fasting liver EDA mRNA. Fasting plasma EDA levels were also assessed. Non-alcoholic fatty liver (NAFL) was defined as >5% hepatic steatosis and nonalcoholic steatohepatitis (NASH) as NAFLD activity score ≥3. Patients were divided into three groups: No NAFLD (n=45); NAFL (n=65); and NASH (n=42). Liver EDA mRNA was increased in patients with NASH compared with No NAFLD (P=0.05), but not NAFL. Plasma EDA levels were increased in NAFL and NASH compared with No NAFLD (P=0.03). Plasma EDA was related to worsening steatosis (P=0.02) and fibrosis (P=0.04), but not inflammation or hepatocellular ballooning. ROC analysis indicates that plasma EDA is not a reliable biomarker for NAFL or NASH. Plasma EDA was not increased in patients with type 2 diabetes and did not correlate with insulin resistance. Together, we show that plasma EDA is increased in NAFL and NASH, is related to worsening steatosis and fibrosis but is not a reliable biomarker for NASH. Circulating EDA is not associated with insulin resistance in human obesity. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.
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Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Ectodisplasinas/sangre , Ectodisplasinas/metabolismo , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Adulto , Biomarcadores/metabolismo , Biopsia , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Inflamación , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/sangre , Obesidad/sangre , Obesidad/complicaciones , Obesidad/metabolismo , ARN Mensajero/metabolismo , Curva ROC , Sensibilidad y EspecificidadRESUMEN
The mucosa microenvironment is critical for intestinal stem cell self-renewal and reconstruction of the epithelial barrier in inflammatory bowel disease (IBD), where the mechanisms underlying cross-talk between intestinal crypts and the microenvironment remain unclear. Here, we firstly identified miR-494-3p as an important protector in colitis. miR-494-3p levels were decreased and negatively correlated with the severity in human IBD samples, as well as in colitis mice. In colitis crypts, a notable cytokine-cytokine receptor, miR-494-3p-targeted EDA2R and the ligand EDA-A2, suppressed colonic stemness and epithelial repair by inhibiting ß-catenin/c-Myc. In differentiated IECs, miR-494-3p inhibits macrophage recruitment, M1 activation and EDA-A2 secretion by targeting IKKß/NF-κB in colitis. A miR-494-3p agomir system notably ameliorated the severity of colonic colitis in vivo. Collectively, our findings uncover a miR-494-3p-mediated cross-talk mechanism by which macrophage-induced intestinal stem cell impairment aggravates intestinal inflammation.
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Colitis/metabolismo , Colon/metabolismo , Ectodisplasinas/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Comunicación Paracrina , Células Madre/metabolismo , Receptor Xedar/metabolismo , Animales , Antagomirs/administración & dosificación , Células Cultivadas , Quimiotaxis , Colitis/genética , Colitis/patología , Colitis/prevención & control , Colon/patología , Modelos Animales de Enfermedad , Ectodisplasinas/genética , Humanos , Quinasa I-kappa B/metabolismo , Mucosa Intestinal/patología , Activación de Macrófagos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Organoides , Nicho de Células Madre , Células Madre/patología , Vía de Señalización Wnt , Receptor Xedar/genéticaRESUMEN
BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is the most common form of ectodermal dysplasia and is mainly associated with mutations in the EDA, EDAR, and EDARADD responsible for the development of ectodermal-derived structures. HED displays different modes of inheritance according to the gene that is involved, with X-linked EDA-related HED being the most frequent form of the disease. METHODS: Two families with tooth agenesis and manifestations of HED underwent clinical examination and EDA, EDAR, and EDARADD genetic analysis. The impact of the novel variant on the protein was evaluated through bioinformatics tools, whereas molecular modeling was used to predict the effect on the protein structure. RESULTS: A novel missense variant was identified in the EDAR (c.287T>C, p.Phe96Ser) of a female child proband and her mother, accounting for autosomal dominant HED. The genetic variant c.866G>A (p.Arg289His) in EDA, which has been previously described, was observed in the male proband of another family confirming its role in X-linked HED. The inheritance model of the missense mutation showed a different relationship with X-linked HED and non-syndromic tooth agenesis. CONCLUSION: Our findings provide evidence of variable expression of HED in heterozygous females, which should be considered for genetic counseling, and different modes of inheritance related to tooth development.
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Anodoncia/genética , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Adulto , Anodoncia/patología , Preescolar , Displasia Ectodérmica/patología , Ectodisplasinas/química , Ectodisplasinas/metabolismo , Receptor Edar/química , Receptor Edar/metabolismo , Femenino , Genes Dominantes , Humanos , Masculino , Mutación Missense , Linaje , Unión Proteica , Dominios Proteicos , Estabilidad Proteica , SíndromeRESUMEN
Androgenetic alopecia (AGA) is a common genetic disorder, and a X-chromosomal locus that contains the androgen receptor (AR) and ectodysplasin A2 receptor (EDA2R) genes represents a major susceptibility locus for AGA. In our previous study, we reported that ectodysplasin-A2 (EDA-A2) induces apoptosis in cultured human hair follicle (HF) cells and promotes the regression of HFs in mice. However, the role of the EDA-A2/EDA2R in AGA remains unknown, as the causative gene in this pathway has not yet been identified and potential functional connections between EDA-A2 signaling and the androgen pathway remain unclear. In this study, we investigated the expression of EDA2R in balding HFs and matched with non-balding HFs. The EDA2R level was upregulated in the balding dermal papilla (DP) cells compared with non-balding DP cells derived from patients with AGA. However, EDA2R was strongly expressed in both balding and non-balding outer root sheath (ORS) cells. We screened EDA-A2-regulated genes in balding DP cells and identified dickkopf 1 (DKK-1) as catagen inducer during the hair cycle. The mRNA and protein expression levels of DKK-1 were both upregulated by EDA-A2. In addition, DKK-1 expression was induced by EDA-A2 both in cultured human HFs and in mouse HFs. Moreover, the EDA-A2-induced apoptosis of DP and ORS cells was reversed by the antibody-mediated neutralization of DKK-1. Collectively, our data strongly suggest that EDA-A2 induces DKK-1 secretion and causes apoptosis in HFs by binding EDA2R, which is overexpressed in the bald scalp. EDA-A2/EDA2R signaling could inhibit hair growth through DKK-1 induction, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of AGA.
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Alopecia/genética , Ectodisplasinas/metabolismo , Folículo Piloso/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Receptor Xedar/metabolismo , Alopecia/metabolismo , Apoptosis , Células Cultivadas , Folículo Piloso/citología , Humanos , Regulación hacia Arriba , Receptor Xedar/genéticaRESUMEN
Transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into spinal cord injury (SCI) may alleviate neuropathic pain and promote functional recovery. The underlying mechanism likely involves activation of glial cells and regulation of inflammatory factors but requires further validation. SCI was induced in 16 ICR mice using an SCI compression model, followed by injection of lentiviral vector-mediated green fluorescent protein- (GFP-) labeled hUC-MSCs 1 week later. Behavioral tests, histological evaluation, and inflammatory factor detection were performed in the treatment (SCI+hUC-MSCs) and model (SCI) groups. Histological evaluation revealed GFP expression in the spinal cord tissue of the treatment group, implying that the injected MSCs successfully migrated to the SCI. The Basso, Beattie, and Bresnahan (BBB) scores showed that motor function gradually recovered over time in both groups, but recovery speed was significantly higher in the treatment group than in the model group. The pain threshold in mice decreased after SCI but gradually increased over time owing to the self-repair function of the body. The corresponding pain threshold of the treatment group was significantly higher than that of the model group, indicating the therapeutic and analgesic effects of hUC-MSCs. Expression of IL-6 and TNF-α in the spinal cord tissue of the treated group decreased, whereas glial cell line-derived neurotrophic factor (GDNF) expression along with ED1 expression increased compared with those in the model group, suggesting that SCI activated ED1 inflammatory macrophages/microglia, which were subsequently reduced by hUC-MSC transplantation. hUC-MSCs are speculated to enhance the repair of the injured spinal cord tissue and exert an analgesic effect by reducing the secretion of inflammatory factors IL-6 and TNF-α and upregulating the expression of GDNF.
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Analgésicos/farmacología , Trasplante de Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal/terapia , Cordón Umbilical/citología , Animales , Ectodisplasinas/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Interleucina-6/metabolismo , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos ICR , Recuperación de la Función/fisiología , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Cardinal symptoms are hypotrichosis, lack of teeth, and hypo- or anhidrosis, but the disease may also evoke other clinical problems. This study aimed at investigating the clinical course of XLHED in early childhood as the basis for an evaluation of the efficacy of potential treatments. METHODS: 25 children (19 boys and 6 girls between 11 and 35 months of age) with genetically confirmed XLHED were enrolled in a long-term natural history study. Clinical data were collected both retrospectively using parent questionnaires and medical records (pregnancy, birth, infancy) and prospectively until the age of 60 months. General development, dentition, sweating ability, ocular, respiratory, and skin involvement were assessed by standardized clinical examination and yearly quantitative surveys. RESULTS: All male subjects suffered from persistent anhidrosis and heat intolerance, although a few sweat ducts were detected in some patients. Sweating ability of girls with XLHED ranged from strongly reduced to almost normal. In the male subjects, 1-12 deciduous teeth erupted and 0-8 tooth germs of the permanent dentition became detectable. Tooth numbers were higher but variable in the female group. Most affected boys had no more than three if any Meibomian glands per eyelid, most girls had fewer than 10. Many male subjects developed additional, sometimes severe health issues, such as obstructive airway conditions, chronic eczema, or dry eye disease. Adverse events included various XLHED-related infections, unexplained fever, allergic reactions, and retardation of psychomotor development. CONCLUSIONS: This first comprehensive study of the course of XLHED confirmed the early involvement of multiple organs, pointing to the need of early therapeutic intervention.
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Displasia Ectodermal Anhidrótica Tipo 1/genética , Antropometría , Preescolar , Displasia Ectodermal Anhidrótica Tipo 1/metabolismo , Displasia Ectodermal Anhidrótica Tipo 1/patología , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Femenino , Genotipo , Humanos , Lactante , Masculino , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
Ectodysplasin is a ligand of the TNF family that plays a key role in ectodermal differentiation. EDA-A1 and EDA-A2 are two isoforms of ectodysplasin that differ only by the insertion of two amino acids and bind to two different receptors, ectodysplasin A receptor (EDAR) and ectodysplasin A2 receptor (EDA2R), respectively. Mutations of EDA-A1 and its receptor EDAR have been associated with hypohidrotic ecodermal dysplasia (HED). However, the role of EDA-A2 and the expression pattern of EDA2R in human hair follicles and in the mouse hair growth cycle have not been reported. In this study, we first investigated the expression of EDA2R in human hair follicles and in cultured follicular cells. EDA2R was strongly expressed in outer root sheath (ORS) cells and weakly expressed in dermal papilla (DP) cells. EDA-A2 induced the apoptosis of both ORS cells and DP cells via the activation of cleaved caspase-3. In addition, EDA2R was highly expressed in the late anagen phase compared with other phases in the hair growth cycle. Moreover, EDA-A2 induced apoptosis in cultured human hair follicle cells and in the mouse hair growth cycle, causing the premature onset of the catagen phase. Collectively, our results suggest that EDA-A2/EDA2R signaling could inhibit hair growth, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of hair loss.
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Ectodisplasinas/farmacología , Folículo Piloso/citología , Receptor Xedar/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Caspasa 3/metabolismo , Células Cultivadas , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Femenino , Folículo Piloso/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Receptor Xedar/genéticaRESUMEN
The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.
Asunto(s)
Displasia Ectodermal Anhidrótica Tipo 1/patología , Ectodisplasinas/genética , Receptor Edar/genética , Simulación de Dinámica Molecular , Proteínas Wnt/genética , Displasia Ectodermal Anhidrótica Tipo 1/genética , Ectodisplasinas/química , Ectodisplasinas/metabolismo , Receptor Edar/química , Receptor Edar/metabolismo , Humanos , Mutación Missense , Linaje , Fenotipo , Estabilidad Proteica , Estructura Terciaria de Proteína , Secuenciación del Exoma , Proteínas Wnt/química , Proteínas Wnt/metabolismoRESUMEN
Braided multi-electrode probes (BMEPs) for neural interfaces comprise ultrafine microwire bundles interwoven into tubular braids. BMEPs provide highly flexible probes and tethers, and an open lattice structure with up to 24 recording/stimulating channels in precise geometries, currently all within a [Formula: see text] diameter footprint. This paper compares the long-term tissue effects of BMEPs ( [Formula: see text] wires) versus single conventional 50- [Formula: see text] wires, by testing nearby chronic immune response and neural survival in rat cortex. Four different types of electrodes were implanted in cortex in each of eight rats: 1) BMEP with tether; 2) tethered 50- [Formula: see text] wire; 3) BMEP without a tether; and 4) untethered 50- [Formula: see text] wire. Quantitative immunohistological statistical comparisons after eight weeks using GFAP, ED1, and NeuN staining clearly showed that both BMEP implants had significantly less tissue immune response and more neuronal survival than either of the 50- [Formula: see text] wires ( ) in each of the eight rats. Data strongly indicate that BMEP tissue responses are superior, and that BMEP designs partly alleviate chronic tissue inflammatory responses and neural losses. The flexible body, tether and open braid lattice, and finer wire diameters of BMEP designs may all contribute to reducing the biological long-term response.
Asunto(s)
Corteza Cerebral/fisiología , Electrodos Implantados , Microelectrodos , Prótesis Neurales , Neuronas/fisiología , Animales , Antígenos Nucleares/metabolismo , Supervivencia Celular , Corteza Cerebral/citología , Corteza Cerebral/inmunología , Ectodisplasinas/metabolismo , Diseño de Equipo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Nanotecnología , Proteínas del Tejido Nervioso/metabolismo , Neuronas/inmunología , Diseño de Prótesis , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Oído Medio/metabolismo , Oído Medio/patología , Displasia Ectodermal Anhidrótica Tipo 1/metabolismo , Displasia Ectodermal Anhidrótica Tipo 1/patología , Ectodisplasinas/metabolismo , Nariz/patología , Transducción de Señal , Animales , Anticuerpos/farmacología , Modelos Animales de Enfermedad , Femenino , Hialina/metabolismo , Masculino , Ratones , Nasofaringitis/complicaciones , Nasofaringitis/patología , Nasofaringe/efectos de los fármacos , Nasofaringe/patología , Otitis Media/complicaciones , Otitis Media/patología , Fenotipo , Ratas , Receptores de la Ectodisplasina/agonistas , Receptores de la Ectodisplasina/metabolismo , Rinitis/complicacionesRESUMEN
Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.
Asunto(s)
Tipificación del Cuerpo , Plumas/citología , Plumas/embriología , Transducción de Señal , Animales , Fenómenos Biomecánicos , Aves/embriología , Agregación Celular , Recuento de Células , Movimiento Celular , Forma de la Célula , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Vuelo Animal/fisiología , Mesodermo/citología , Mesodermo/embriología , Piel/citología , Piel/embriología , beta Catenina/metabolismoRESUMEN
Ectodysplasin receptor EDAR is seen as a typical Tumor Necrosis Factor receptor (TNFR) family member known to interact with its ligand Eda-A1, and signaling mainly through the nuclear factor-kappaB (NF-κB) and c-jun N-terminal kinases pathways. Mutations in genes that encode proteins involved in EDAR transduction cascade cause anhidrotic ectodermal dysplasia. Here, we report an unexpected pro-apoptotic activity of EDAR when unbound to its ligand Eda-A1, which is independent of NF-κB pathway. Contrarily to other death receptors, EDAR does recruit caspase-8 to trigger apoptosis but solely upon ligand withdrawal, thereby behaving as the so-called dependence receptors. We propose that pro-apoptotic activity of unbound EDAR confers it a tumor suppressive activity. Along this line, we identified loss-of-pro-apoptotic function mutations in EDAR gene in human melanoma. Moreover, we show that the invalidation of EDAR in mice promotes melanoma progression in a B-Raf mutant background. Together, these data support the view that EDAR constrains melanoma progression by acting as a dependence receptor.