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

Abstract

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.

Unilateral zebrafish corneal injury induces bilateral cell plasticity supporting wound closure

“…We have previously shown that murine corneal wound closure is based on cell rearrangements 9 . We have shown as well that tear composition is quickly modified following corneal injury, to support corneal healing 10 . These changes in the corneal microenvironment, are crucial for proper wound closure, by supplying a new combination of factors via the tears when necessary.…”

“…One of the most interesting findings of our study is the bilateralization of corneal response to an unilateral injury. We ourselves have previously reported the bilateralization of lacrimal gland response in mice after abrasion 10 . Other studies on murine and human cornea have also described such a phenomenon 59 , 60 .…”

Unilateral corneal insult in Zebrafish results in a bilateral cell shape and identity modification, supporting wound closure

“…Our previous work demonstrated the bilateralization of lacrimal gland response to unilateral corneal abrasion in mouse (Kuony et al, 2019). Unexpectedly, this response coordination on both sides seemed to play an important role as it is evolutionary conserved.…”

“…The fish were anesthetized with 0.02% Tricaine (A5040 Sigma) and placed into an incision on a moist sponge, head protruding from the sponge surface. Corneal epithelium wounding was performed as in (Kalha et al, 2018a/b, Kuony et al, 2019) using an ophthalmic burr (Algerbrush II) with 0.5 mm diameter tip and applying moderate pressure on the eye surface. After abrasion, the fish were transferred to tank water for recovery.…”

“…In case of a deeply embedded foreign object, corneal irregularities might form, resulting in significant visual disruption. Previously, we showed that murine corneal wound closure was based on cell rearrangements (Kalha et a.l, 2018a), and tear composition was quickly modified after corneal insult (Kuony et al, 2019). These changes in corneal microenvironment, undoubtly supporting corneal healing, were crucial for proper wound closure, by bringing a new mix of factors through the tears when needed, for instance to support corneal wound healing after insult.…”