Mechanisms that specify subtypes of photoreceptors for color vision

Project Summary/Abstract Color vision requires the expression of opsins with different wavelength sensitivities in specific subtypes of photoreceptor (PR) neurons. The molecular mechanisms that control these spatially precise, PR subtype- specific expression patterns remain poorly understood. The long-term goal of the proposed project is to use the Drosophila melanogaster retina as a model to decipher the cis-regulatory mechanisms and identify conserved trans-acting factors that specify different subtypes of PR neurons for color vision. We recently discovered that the gene regulatory network that mediates a blue- vs. green-sensitive PR fate decision in the Drosophila retina involves the orthologs of four conserved transcription factors (Otd/Otx2/Crx, Tj/Nrl, Hr3/Rorβ, and Blimp-1/Prdm1) that promote rod PR fate in the mammalian eye and have been associated with severe human retinopathies. In the current proposal, we will determine how a binary switch controls the blue- vs. green-sensitive PR fate decision through a differential regulation of the conserved Hippo tumor suppressor pathway. In preliminary experiments, we discovered that the conserved transcription factor H6-like-homeobox (Hmx/HMX1-3) is specifically expressed in blue PRs, where it promotes blue PR fate by repressing the Hippo pathway as a crucial component of a positive feedback loop. Notably, Hmx’s human ortholog HMX1 has been associated with severe eye and ear defects known as Oculoauricular Syndrome. We will unravel how Hmx interacts with core components of the Hippo pathway and identify its genomic targets (Aim 1). Moreover, we will investigate how a transient developmental signal is transduced into a permanent subtype-specific Hmx activation and decipher the underlying cis- regulatory logic (Aim 2). Lastly, we will investigate the role of cofactors in Hmx’s functions in different ocular contexts and analyze the functions of Hmx’s highly conserved domains (Aim 3). In conclusion, the proposed studies are significant and innovative because they will yield fundamental insights into the regulatory logic of opsin expression and photoreceptor diversity by elucidating how cis- regulatory mechanisms and conserved trans-acting factors, which have been associated with human retinopathies, generate different subtypes of photoreceptor neurons for color vision.