Pharmacological Stimulation of Edar Signaling in the Adult Enhances Sebaceous Gland Size and Function

Kowalczyk‐Quintas, Christine; Schuepbach‐Mallepell, Sonia; Willen, Laure; Smith, Terry; Huttner, Kenneth; Kirby, Neil; Headon, Denis J.; Schneider, Pascal

doi:10.1038/jid.2014.382

Cited by 12 publications

(7 citation statements)

References 49 publications

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“…The Eda −/− mouse strain provides an interesting model in which to study DEDs. Although LG implication in XLHED-related dry eye phenotype was reported in dog (Casal et al, 2007), and suggested in mice (Grüneberg, 1971;Kowalczyk-Quintas et al, 2015), dry eye symptoms have so far been attributed to atrophy or agenesis of Meibomian glands, resulting in an accelerated tear film evaporation in the murine model (Wang et al, 2016). In contradiction to a recent study (Wang et al, 2016), our tabby strain displayed a lower tear film volume, hinting at LG involvement in XLHED-related dry eye phenotype in our model.…”

Section: Discussioncontrasting

confidence: 89%

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

et al. 2019

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A lack of ectodysplasin-A (Eda) signaling leads to dry eye symptoms, which have so far only been associated with altered Meibomian glands. Here, we used loss-of-function (Eda −/−) mutant mice to unravel the impact of Eda signaling on lacrimal gland formation, maturation and subsequent physiological function. Our study demonstrates that Eda activity is dispensable during lacrimal gland embryonic development. However, using a transcriptomic approach, we show that the Eda pathway is necessary for proper cell terminal differentiation in lacrimal gland epithelium and correlated with modified expression of secreted factors commonly found in the tear film. Finally, we discovered that lacrimal glands present a bilateral reduction of Eda signaling activity in response to unilateral corneal injury. This observation hints towards a role for the Eda pathway in controlling the switch from basal to reflex tears, to support corneal wound healing. Collectively, our data suggest a crucial implication of Eda signaling in the cornea-lacrimal gland feedback loop, both in physiological and pathophysiological conditions. Our findings demonstrate that Eda downstream targets could help alleviate dry eye symptoms.

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Section: Discussioncontrasting

confidence: 89%

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

et al. 2019

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“…Reports of EDAR expression in adult murine skin ( Fessing et al., 2006 , Kowalczyk-Quintas et al., 2015 ) suggested an active role for EDA/EDAR signaling postnatally. Given that the role of EDA/EDAR signaling is predominantly in the rearrangement of the epidermis into placodes during development ( Ahtiainen et al., 2014 , Mustonen et al., 2004 , Schmidt-Ullrich et al., 2006 ), we focused on epithelial aspects of the wound phenotype, reporting EDAR-dependent changes in both peri-wound proliferation and re-epithelialization.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, few studies have explored potential roles for EDAR signaling in adult tissue. Kowalczyk-Quintas et al. (2015) recently showed that Edar is expressed within the sebaceous glands of adult mice, and Inamatsu et al.…”

Section: Introductionmentioning

confidence: 99%

Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair

Garcin

Huttner

Kirby

et al. 2016

Journal of Investigative Dermatology

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The highly conserved ectodysplasin A (EDA)/EDA receptor signaling pathway is critical during development for the formation of skin appendages. Mutations in genes encoding components of the EDA pathway disrupt normal appendage development, leading to the human disorder hypohidrotic ectodermal dysplasia. Spontaneous mutations in the murine Eda (Tabby) phenocopy human X-linked hypohidrotic ectodermal dysplasia. Little is known about the role of EDA signaling in adult skin homeostasis or repair. Because wound healing largely mimics the morphogenic events that occur during development, we propose a role for EDA signaling in adult wound repair. Here we report a pronounced delay in healing in Tabby mice, demonstrating a functional role for EDA signaling in adult skin. Moreover, pharmacological activation of the EDA pathway in both Tabby and wild-type mice significantly accelerates healing, influencing multiple processes including re-epithelialization and granulation tissue matrix deposition. Finally, we show that the healing promoting effects of EDA receptor activation are conserved in human skin repair. Thus, targeted manipulation of the EDA/EDA receptor pathway has clear therapeutic potential for the future treatment of human pathological wound healing.

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“…Thus, the corrective actions of mAbEDAR can be explained by its ability to counteract the effect of reduced EDAR expression caused by the absence of Pax9. This conclusion is supported by the findings that the size of the sebaceous glands and the amount of sebum secretion in Eda-deficient animals exceeds that of the wildtype littermates receiving identical doses of mABEDAR1 (Kowalczyk-Quintas et al 2015). Hence, EDAR activity in Pax9 −/− mice treated with mAbEDAR can restore Eda signaling to functional levels and result in closure of the palatal shelves, as shown by the outgrowth of the palatal shelves and bone deposition toward the midline.…”

Section: Discussionmentioning

confidence: 69%

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9^-/- Mice

Song

Zhou

et al. 2017

J Dent Res

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To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9 mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9 embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.

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Pharmacological Stimulation of Edar Signaling in the Adult Enhances Sebaceous Gland Size and Function

Cited by 12 publications

References 49 publications

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9^-/- Mice

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Pharmacological Stimulation of Edar Signaling in the Adult Enhances Sebaceous Gland Size and Function

Cited by 12 publications

References 49 publications

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair

Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice

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Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9^-/- Mice