By Dirk Hoffman
Published August 30, 2023
The National Institutes of Health grant is for $2.3 million over five years and represents the third funding cycle of one of Mu’s NIH grants through a competitive renewal application. Mu conducts his research at the Ross Eye Institute.
The renewal funds years 11 through 15 of the grant that originated in 2011. The study is titled “Regulatory Mechanisms for Retinal Ganglion Cell Genesis.”
“The retina is a thin neural tissue in our eye and functions to receive visual signals (light) and send them to the brain,” says Mu, principal investigator on the grant. “This function is carried out by many cell types, or neurons, in the retina.”
“The proposed project studies how one of the cell types, retinal ganglion cells (RGC), is generated during embryonic development,” he adds. “This study is aimed at understanding how key regulating proteins (transcription factors) interact with and modify the status of chromatin in the cell and promote RGC differentiation.”
Mu points out that retinal ganglion cells are the only cell type connecting the retina to the brain via the optic nerve and are affected in many retinal diseases.
“The findings from the proposed experiments will lead to further insights into the molecular basis underpinning the generation of this important retinal cell type and offer guidance for developing strategies to treat degenerative retinal diseases such as glaucoma,” he says.
During embryonic development, the various retinal cell types all originate from a common pool of retinal progenitor cells (RPCs), although individual cell types are born in distinct time windows, Mu says.
“How individual retinal cell types arise from RPCs is an active field of research, as it is critical to understanding the generation of cellular diversity in the retina and developing therapeutic strategies to treat degenerative retinal diseases,” he adds.
Mu notes that many transcription factors involved in the generation of individual retinal cell types have been identified and his lab has made major discoveries in understanding their functions using state-of-the-art technologies.
“Single cell technologies have led to unprecedented progress in discerning the cellular relationships of the different lineage trajectories and the underlying changes in the epigenetic landscape,” he adds.
“The roles of individual transcription factors in shaping the epigenetic landscape to drive multipotent RPCs to specific fates are also beginning to be revealed.”
One of the major findings from the single cell RNA-seq (scRNA-seq) studies is that all the retinal lineage trajectories go through a shared state, namely transitional RPCs (tRPCs), before fate determination, Mu explains.
tRPCs are multipotent and co-express genes involved in the different retinal cell types such as Atoh7 for retinal ganglion cells (RGCs) and Otx2 and Neurod1 for photoreceptors, but how individual cell fates is decided remains unknown, he adds.
“Our long-term objective is to understand the mechanisms controlling RGC genesis,” Mu says. “In this application, we propose to address several key knowledge gaps regarding the emergence of the RGC lineage from tRPCs.”
“The first is the missing branch of upstream inputs as indicated by scRNA-seq analysis of the Atoh7-null retina. We hypothesize that the some candidate factors fulfill this role by functioning in parallel with Atoh7 to promote RGC genesis.”
“The second gap we aim to address is the molecular basis for the specificity of Atoh7 for the RGC lineage. This is based on the fact that multiple proneural bHLH transcription factors are expressed in the retina, but only Atoh7 promotes RGC formation.”
Tao Liu, PhD, associate professor of oncology at Roswell Park Comprehensive Care Center, and research associate professor of biochemistry at the Jacobs School, is a co-investigator on the study.