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 gland...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2019-04-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/12/4/dmm037804 |
| _version_ | 1818616968400338944 |
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| author | Jorge del-Pozo Neil MacIntyre Ali Azar Denis Headon Pascal Schneider Michael Cheeseman |
| author_facet | Jorge del-Pozo Neil MacIntyre Ali Azar Denis Headon Pascal Schneider Michael Cheeseman |
| author_sort | Jorge del-Pozo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T16:58:14Z |
| format | Article |
| id | doaj.art-ced1855e543343a8bacfa69e06142629 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-16T16:58:14Z |
| publishDate | 2019-04-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-ced1855e543343a8bacfa69e061426292022-12-21T22:23:49ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-04-0112410.1242/dmm.037804037804Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasiaJorge del-Pozo0Neil MacIntyre1Ali Azar2Denis Headon3Pascal Schneider4Michael Cheeseman5 Veterinary Pathology, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK Veterinary Pathology, The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK Developmental Biology Division, Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK Developmental Biology Division, Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK Department of Biochemistry, University of Lausanne, Boveresses 155, CH-1066 Epalinges, Switzerland Developmental Biology Division, Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK 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.http://dmm.biologists.org/content/12/4/dmm037804EDAR signallingEda mouseEdaradd ratXLHEDAuditory-tube submucosal glandOtitis media |
| spellingShingle | Jorge del-Pozo Neil MacIntyre Ali Azar Denis Headon Pascal Schneider Michael Cheeseman Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia Disease Models & Mechanisms EDAR signalling Eda mouse Edaradd rat XLHED Auditory-tube submucosal gland Otitis media |
| title | Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| title_full | Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| title_fullStr | Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| title_full_unstemmed | Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| title_short | Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| title_sort | role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia |
| topic | EDAR signalling Eda mouse Edaradd rat XLHED Auditory-tube submucosal gland Otitis media |
| url | http://dmm.biologists.org/content/12/4/dmm037804 |
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