Embryonic hyperglycemia perturbs the development of specific retinal cell types, including photoreceptors

Abstract

Diabetes is linked to various long-term complications in adults, such as neuropathy, nephropathy, and diabetic retinopathy. Diabetes poses additional risks for pregnant women, because glucose passes across the placenta, and excess maternal glucose can result in diabetic embryopathy. While many studies have examined the teratogenic effects of maternal diabetes on fetal heart development, little is known about the consequences of maternal hyperglycemia on the development of the embryonic retina. To address this question, we investigated retinal development in two models of embryonic hyperglycemia in zebrafish. Strikingly, we found that hyperglycemic larvae displayed a significant reduction in photoreceptors and horizontal cells, whereas other retinal neurons were not affected. We also observed reactive gliosis and abnormal optokinetic responses in hyperglycemic larvae. Further analysis revealed delayed retinal cell differentiation in hyperglycemic embryos that coincided with increased reactive oxygen species (ROS). Our results suggest that embryonic hyperglycemia causes abnormal retinal development via altered timing of cell differentiation and ROS production, which is accompanied by visual defects. Further studies using zebrafish models of hyperglycemia will allow us to understand the molecular mechanisms underlying these effects.

Embryonic Hyperglycemia Delays the Development of Retinal Synapses in a Zebrafish Model

“…Previous studies demonstrated abnormal retinal development in hyperglycemic zebrafish embryos [ 7 , 8 ]. While the decreased number of photoreceptors, horizontal cells, and ganglion cells corresponded to altered retinal thickness in these embryos, it remained unclear whether the reduced number of retinal cells alone accounted for the observed visual defects or whether there existed any defects in the development of retinal synapses in this model.…”

“…The aquatic zebrafish environment can be manipulated to study the specific effects of a chemical agent on embryo development, which is external, rapid, and easily visualized. For example, immersion of zebrafish in water containing high glucose results in the developmental changes of hyperglycemia [ 7 , 8 ], thereby facilitating our study of these changes. Overall, their relatively easy maintenance, high fecundity, small size, and manipulatable environment make zebrafish an excellent model for vertebrate developmental biology.…”

“…Two recent studies reported abnormal retinal development in hyperglycemic zebrafish embryos [ 7 , 8 ]. Although altered retinal thickness corresponds to decreased numbers of photoreceptors, horizontal cells, and ganglion cells in hyperglycemic zebrafish embryos, it remains unclear whether these embryos exhibit any other deficits in the establishment of retinal synapses that would result in the observed visual defects [ 7 , 8 ]. The fundamental process of developmental synaptogenesis builds neural circuits in the brain.…”

“…In the zebrafish, the cone mosaic presence in the ventral retina is found 54 h post-fertilization (hpf) [ 9 ], and the rod terminals are visible as early as 5 dpf [ 10 ]. Interestingly, recent studies, using both genetic and nutritional models of embryonic hyperglycemia, found that rod and cone photoreceptor cells are significantly decreased [ 8 ]. Thus, any changes we report in the OPL synapse development in the current studies may apply to rod and cone photoreceptors similarly.…”

Embryonic nutritional hyperglycemia decreases cell proliferation in the zebrafish retina

“…While there is a major focus on the study of juvenile/adult DR, the effects of hyperglycemia during early retinal development are less well studied. Recent works in embryonic zebra sh models of nutritional hyperglycemia revealed that hyperglycemia leads to decreased cell numbers of mature retinal cell types, which has been related to a modest increase in apoptotic cell death and altered cell differentiation (Singh et al 2019;Titialii-Torres and Morris 2022). However, how embryonic hyperglycemia impacts cell proliferation in developing retinas remains still unknown.…”