Integrative and rapid discovery of retinal regulatory molecules

Abstract

Purpose : Retinal neurons relay visual information by forming precise circuits in which hundreds of individual neurons connect with appropriate wiring partners. Despite this remarkable complexity, relatively few genes have been directly linked to retinal circuit organization due to a lack of methods to rapidly identify neural wiring molecules in mammals.

Methods : Here, we report the establishment of a pipeline for the Identification of vascular and Neural integrity Genes by High Throughput screening (INSiGHT). Using this system, we have characterized 90 mutant mouse lines and over 400 individual animals. This approach leverages the resources available through the Knockout Mouse Project (KOMP) and evaluates central components of retina structure, including: 1) gene expression patterns, 2) vessel and cellular topographic patterning, and 3) neuron and synaptic arrangement.

Results : Using this system, we have identified 14 unique genes required for neuronal, neurovascular, and synaptic organization in mouse retina. These genes control distinct aspects of cellular function, with the majority regulating cellular structure, protein transport or function, and gene expression. An interesting subset also regulates neurotransmitter formation or release. The majority of the identified genes are novel, having not previously been implicated as retinal regulatory molecules in mouse nor identified in similar screens in flies and zebrafish.

Conclusions : These data expand the genetic landscape involved in retinal circuit organization. They also provide a road map for continued discovery of mammalian retinal regulators that may aid in the identification and characterization of new retina disease causing alleles.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.