Progressive myoclonic epilepsy-associated geneKctd7regulates retinal neurovascular patterning and function

Abstract

AbstractNeuron function relies on and instructs the development and precise organization of neurovascular units that in turn support circuit activity. However, our understanding of the molecular cues that regulate this relationship remains sparse. Using a high-throughput screening pipeline, we recently identified several new regulators of vascular patterning. Among these was the potassium channel tetramerization domain-containing protein 7 (KCTD7). Mutations inKCTD7are associated with progressive myoclonic epilepsy, but how KCTD7 regulates neural development and function remains poorly understood. To begin to identify such mechanisms, we focus on mouse retina, a tractable part of the central nervous system that contains precisely ordered neuron subtypes supported by a trilaminar intravascular network. We find that deletion ofKctd7results in defective patterning of the adult retina vascular network, resulting in increased branching, vessel length, and lacunarity. These alterations reflect early and specific defects in vessel development, as emergence of the superficial and deep vascular layers were delayed. These defects are likely due to a role for Kctd7 in inner retina neurons. Kctd7 it is absent from vessels but present in neurons in the inner retina, and its deletion resulted in a corresponding increase in the number of bipolar cells in development and increased vessel branching in adults. These alterations were accompanied by retinal function deficits. Together, these data suggest that neuronal Kctd7 drives growth and patterning of the vasculature and suggest that neurovascular interactions may participate in the pathogenesis of KCTD7-related human diseases.Alevy et al. HighlightsKctd7 is required for normal retinal vascular organization and retinal function in adults.Deletion ofKctd7disrupts the emergence of the superficial and deep vessel layers.Kctd7 may impact vascular patterning through influencing neurons as it is expressed in and regulates bipolar cells.Kctd7 driven neurovascular interactions may participate in the pathogenesis of KCTD7-related human diseases.Lay SummaryNeuron function requires an organized vasculature to maintain brain health and prevent disease, but many neurovasculature regulatory genes remain unknown. Alevy et al. identify the progressive myoclonic epilepsy-associated geneKctd7as a key regulator of vascular development and retinal function. They further show that Kctd7 regulation of vessel patterning likely occurs downstream of its role in regulating the development or activity of specific neuron types. These data suggest that KCTD7-regulated neurovascular interactions may participate in the pathogenesis of associated human diseases.