Humans rely on sight, which is primarily mediated by three color-sensing cone types, to perceive the world in a kaleidoscope of hues. Blue cones develop earliest, followed by the morphologically indistinguishable green and red cones.Researchers have debated if green and red cone determination is random or deliberate.

          Headshot of Sarah Hadyniak
Sarah Hadyniak is a postdoctoral researcher at Duke University, where she studies retinas.
Sarah Hadyniak

In a recent study, Sarah Hadyniak, a developmental biologist at Duke University, explored the mechanisms that drive green and red cone generation.2 Understanding cone fate signaling could help researchers with modeling retinal systems and advancing therapies for vision impairments.

Green cones detect medium (M) wavelengths, while red cones detect long (L) wavelengths of light. The only known difference between M and L cones is the expression of opsin. Hadyniak’s team used colorimetric in situ hybridization probes to distinguish ­between M-opsin and L-opsin mRNA expression. 

“[Our system] was a big milestone in being able to see what was going on with the cones,” said Hadyniak. 

The team assessed the timing of M and L cone development in human fetal retinas. The fetal retinas expressed M-opsin before L-opsin. Adult retinas expressed both opsinsindicating that green cones developed first. 

Next, the researchers examined the role of retinoic acid, which is known to influence photoreceptor development in zebrafish. The team noted high expression of RA synthesis genes early in human retinal organoid development that decreased over time, similar to what occurs in zebrafish.

To test whether RA promoted M or L cones, Hadyniak generated human retinal organoids and administered RA over various differentiation timeframes. Early administration of RA yielded organoids with almost exclusively M cones, while late RA infusion predominantly produced L cones. 

“Cones are particularly interesting as the cell type that matters most for our daily operation in color vision,” said Rui Chen, a molecular geneticist at Baylor College of Medicine who was not involved in the study. “[This study] is informative for understanding the developmental mechanism.”


  1. Eldred KC, et al. Science. 2018;362(6411):eaau6348.
  2. Hadyniak SE, et al. PLoS Biol. 2024;22(1):e3002464.
  3. Chinen A, et al. Genetics. 2003;163(2):663-675.