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

Wilmet, B.; Michiels, C.; Zhang, J.; Louboutin, A.; Boranijasevic, S.; Frederiksen, H.; Callebert, J.; Varin, J.; Gimenez, M. L.; Morgans, C. W.; Duvoisin, R.; Horan, L.; Plevin, R.; Picaud, S.; Marre, O.; Audo, I.; Zeitz, C.

doi:10.1101/2025.09.29.678242

bioRxiv · 10.1101/2025.09.29.678242

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

Wilmet, B.·Michiels, C.·Zhang, J.·Louboutin, A.·Boranijasevic, S.·Frederiksen, H.·Callebert, J.·Varin, J.·Gimenez, M. L.·Morgans, C. W.·Duvoisin, R.·Horan, L.·Plevin, R.·Picaud, S.·Marre, O.·Audo, I.·Zeitz, C.

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Abstract

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 RGC responses to light flashes. These data provide insights into retina-driven mechanisms of myopization, nuancing the impact of ON and OFF pathways upon emmetropization.

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Wilmet, B., Michiels, C., Zhang, J., Louboutin, A., Boranijasevic, S., Frederiksen, H., Callebert, J., Varin, J., Gimenez, M. L., Morgans, C. W., Duvoisin, R., Horan, L., Plevin, R., Picaud, S., Marre, O., Audo, I., Zeitz, C.. 2025-10-01. Increased sensitivity to myopia and altered retinal ON/OFF balance in a mouse model lacking Dusp4. https://doi.org/10.1101/2025.09.29.678242

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