The goal of the Emerson Lab is to understand the molecular and cellular mechanisms that underlie the development of the vertebrate retina. In particular we focus on cone photoreceptors, which are the cells that mediate the first steps in high acuity and color vision.
Despite their functional importance, our knowledge of the developmental mechanisms involved in cone photoreceptor generation and subsequent differentiation are poorly understood. Some of the questions we seek to answer are as follows:
What are the gene-regulatory networks that promote cone photoreceptor genesis from retinal progenitor cells?
How is the generation of other cell types coordinated with that of cones?
How are cones and the other major photoreceptor type (rods) related developmentally?
By addressing these questions, we will lay the foundation for the development of new therapies for the treatment of retinal diseases with cone photoreceptor loss. This will include new strategies for the de novo generation of cones from stem cells or in vivo retinal cell populations.
To study the early events in cone photoreceptor genesis, we primarily use a cis-regulatory approach. Cis-regulatory modules, also known as enhancers, are pieces of DNA that recruit sequence-specific transcription factors and affect the regulation of transcription. Candidate enhancers for genes involved in cone photoreceptor genesis or other retinal cell types are identified bioinformatically and tested for the ability to drive cell type specific reporter expression.
Electroporation of reporter constructs into retinal cells in vivo or ex vivo is our preferred method of analysis because of the relative ease, cost, expediency, and reliability of this method. These cis-regulatory modules serve as tools to probe the architecture of genetic regulatory networks, allow for the identification of transient states of cell fate and the targeted isolation of these populations for transcriptome analysis.
Retinal Progenitor Cells with Restricted Cell Fate Potential
Using a cis-regulatory approach, we have recently identified a cis-regulatory element active in a subset of retinal progenitors that preferentially generate cone photoreceptors and horizontal cells. This led us to identify the Otx2 and Onecut1 transcription factors as key co-regulators of this retinal progenitor type. We are currently using whole transcriptome analysis and further cis-regulatory studies to identify the genetic programs that establish this cell state, promote the fates of its daughter cells, and repress alternative retinal fates such as rod photoreceptors.