Increased sensitivity to myopia and altered retinal ON/OFF balance in a mouse model lacking Dusp4

Myopia, influenced by environmental and genetic factors, occurs when the emmetropization process fails to stop, causing excessive eyeball growth. Highly myopic animal models lacking a functional ON-pathway identified Dusp4 as a potential gene implicated in myopia. Here, we used a mouse model lacking DUSP4 to gain a better understanding of its retinal role and the mechanisms implicated in myopia development.

Dusp4-/- mice have a reduced basal level of retinal dopamine and a higher susceptibility to lens-induced myopia. Dusp4 is expressed in ON-bipolar cells and a subset of OFF-bipolar cells in a light dependent manner. The absence of DUSP4 causes a hyperactivation of the MAPK/ERK pathway.

Dusp4-/- mice showed reduced optomotor responses, increased ON-bipolar cell depolarization, reduced oscillatory potentials together with altered OFF and ON-OFF retinal ganglion cell responses to light flashes. These data provide insights into retina-driven mechanisms of myopization, nuancing the impact of ON and OFF pathways upon emmetropization. The authors are grateful to Manuel Simonutti, Julie Dégardin, Pauline Abgrall, and Marion Cornebois for their valuable help in phenotyping (platform at the Institut de la Vision).

The authors are thankful to Julie Geus, Raja Rabia, Wissam Afyass and Lisa-Léa Rota for the mouse handling and housing (Janvier labs®). The authors are thankful to Christophe Tourain for creating the frames for LIM experiments. Supported by Agence Nationale de la Recherche (ANR-22-CHIN-0006) (OM, CZ); Banque publique d'investissement (PREMYOM) (OM, CZ), Retina France (CZ); Valentin Haüy and AFM (CZ), IRPINSERM (CZ and RD); Prix Dalloz pour la recherche en ophtalmologie and Fondation Dalloz—Institut de France (CZ); Fondation Voir et Entendre (CZ); Fondation de l’oeil—Fondation de France (IA, CZ), Ville de Paris and Region Ile de France; Labex Lifesenses (reference ANR-10-LABX-65) (IA, CZ), supported by French state funds managed by the ANR within the Investissements d’Avenir programme (ANR-11-IDEX-0004-0); the Programme Investissements d’Avenir IHU FOReSIGHT (ANR-18-IAHU-01) (IA, CZ); National Institutes of Health grant R01EY029985 (RD, CWM); funded by the European Union under Grant Agreement #101119501 (SB).

The MyoTreat Consortium (https://www.myotreat.eu/), supported by the European Union under Project 101119501 (MyoTreat-HORIZON-MSCA-2022-DN-01), List of Myotreat participant can be found in Supplemental Information file. These authors contributed equally: Baptiste Wilmet, Christina Zeitz. Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France Baptiste Wilmet, Christelle Michiels, Jingyi Zhang, Awen Louboutin, Sanja Boranijasevic, Helen Frederiksen, Juliette Varin, Marie-Laure Gimenez, Said El Shamieh, Serge Picaud, Olivier Marre, Isabelle Audo & Christina Zeitz Service of Biochemistry and Molecular Biology, INSERM U942, Hospital Lariboisière, APHP, Paris, France Molecular Testing Laboratory, Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA CHNO des Quinze-Vingts, Centre de Référence Maladies Rares, Paris, France Correspondence to Baptiste Wilmet or Christina Zeitz.

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