New Mechanisms Found in Retinal Neuron Development

A study led by Tiffany Schmidt, Ph.D., Associate Professor of Ophthalmology and Neurobiology at the Weinberg College of Arts and Sciences, has uncovered previously unknown cellular mechanisms that define neuron identity in retinal cells. The findings, published in Nature Communications, offer valuable insight into the molecular processes that govern retinal neuron specialization and may enhance the broader understanding of brain circuitry and neurological diseases.

Focus on Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs)

Schmidt’s research centers on melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), a specialized class of neurons in the retina responsible for synchronizing the body’s circadian rhythm with light-dark cycles.

There are six known subtypes of ipRGCs, designated M1 through M6, each expressing different levels of the melanopsin protein. This protein enables ipRGCs to respond directly to light, but until now, the mechanisms driving the structural and functional distinctions between these subtypes had remained unclear.

“We've been wondering how you can get this one ipRGC that morphs into all these different classes and how they're then specialized for all their different behaviors,” said Schmidt.

Investigating the Role of BRN3B in Neuronal Specialization

In collaboration with the laboratory of Yue Yang, Ph.D., Assistant Professor of Neurobiology, Schmidt's team employed a combination of electrophysiological analysis and genetic sequencing to study the role of a protein called BRN3B in ipRGC development. Using knockout mouse models, the researchers explored how the absence of BRN3B affects gene regulation across ipRGC subtypes.

“Notably, BRN3B expression is present in newly postmitotic ipRGCs and persists into adulthood, suggesting it may play as-yet-unidentified roles in ipRGC development and function,” the authors wrote.

Their results revealed that the removal of BRN3B led to significant transcriptional and functional shifts in all ipRGC subtypes. Most strikingly, all subtypes adopted gene expression profiles resembling those of M1 cells, highlighting BRN3B’s role in maintaining subtype-specific identities.

Broader Implications for Retinal and Neurological Research

These discoveries shed new light on the developmental pathways that shape neuronal identity, helping to explain how different retinal neurons acquire their distinct molecular and functional characteristics.

“If we can understand how these features are tuned during development in this class of six cells across such a broad range, now we can start to see what's downstream of that and what are the basic mechanisms that might be present in other diverse types of neurons in the retina, but also in the brain as well,” Schmidt explained.

Future Directions in Understanding Neuronal Function

Looking ahead, the research team aims to identify the intracellular signaling mechanisms and downstream genetic targets influenced by BRN3B, in order to further elucidate how distinct neuronal properties are shaped.

“I think that will be very exciting for our understanding of what types of mutations can affect neuron function, which would have implications for diseases beyond the retina,” Schmidt added.

Reference:

Marcos L. Aranda et al, Genetic tuning of retinal ganglion cell subtype identity to drive visual behavior, Nature Communications (2025). DOI: 10.1038/s41467-025-63675-w