Loss of vision associated with diseases such as glaucoma, optic nerve hypoplasia, and diabetic retinopathy is in part caused by the dysfunction and/or premature death of retinal ganglion cells (RGCs), which transmit all visual information from the eye to the brain. As such, the development of therapies to regenerate RGCs and re-establish their central connections is a high priority. Visual perception is mediated by integrating inputs of distinct subtypes of neurons, each of which monitor different aspects of the visual scene, a phenomenon referred to as parallel processing. The exquisite tuning of individual neurons arises via selective synapse formation between specific subtypes at each stage of visual processing. Though the presence and importance of parallel circuits in the visual system are well established, the molecular logic underlying their assembly remains poorly understood. To bridge this gap in knowledge, we performed a targeted screen to identify molecules that may regulate parallel circuit connectivity between retinal ganglion cells (RGCs) and visual neurons in the superior colliculus (SC). In this proposal, we will explore the role of hedgehog interacting protein (HHIP), which emerged as a top candidate based on its spatially- and temporally-restricted expression pattern in the SC and previous evidence implicating hedgehog family members in RGC axon guidance. First, we will test the hypothesis that HHIP is required for the proper targeting of specific subtypes of RGCs in the SC. Second, we will determine the mechanism by which HHIP guides RGCs by performing in vitro assays on isolated RGCs. Third, we will test the hypothesis that HHIP is required for the development of specific visual subcircuits by determining the visual response properties of SC neurons in mice lacking HHIP expression. Finally, we will elucidate the morphological and functional properties of HHIP+ neurons in the SC by leveraging a novel transgenic mouse line to label these cells. Taken together, the proposed experiments will elucidate a novel role for HHIP in neural development and provide critical insight into the poorly understood process of parallel circuit formation.

Public Health Relevance

Developmental and age-related visual disorders, such as diabetic retinopathy, glaucoma and optic nerve hypoplasia, affect retinal ganglion cells (RGCs), which convey all visual information to the brain. An attractive therapeutic strategy is to regenerate lost RGCs and their precise connections in the brain; however, our understanding of the molecular processes underlying such connectivity is significantly lacking. In this proposal, we will use a combination of in vivo anatomical and electrophysiological methods in unique transgenic and knockout mouse models and in vitro assays on cultured RGCs to elucidate novel molecular mechanisms by which precise connectivity is established in the visual system.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section (SPC)
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Greenwell, Thomas
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Children's Research Institute
United States
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