Making mice with enhanced color vision

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"If you gave mice a new sensory input at the front end, could their brains learn to make use of the extra data at the back end?" asks Jeremy Nathans M.D., Ph.D., professor of molecular biology and genetics, neuroscience, and ophthalmology at Hopkins. "The answer is, remarkably, yes. They did not require additional generations to evolve new sight."

Retinas of primates such as humans and monkeys are unique among mammals in that they have three visual receptors that absorb short (blue), medium (green) and long (red) wavelengths of light. Mice, like other mammals, only have two; one for short and one for medium wavelengths.

In the study, the researchers designed a "knock-in" mouse that has one copy of its medium wavelength receptor replaced with the human long wavelength receptor, so both were expressed in the retina. The human receptors were biologically functional in the mice, but the real question was whether the mice could use the new visual information.

To address this question, the researchers used a classic preference test; mice set before three light panels were trained to touch the one panel that appeared to differ from the other two. A correct answer was rewarded with a drop of soy milk.

To circumvent thorny issues related to the subjective nature of color perception — everyone who has had a discussion as to whether the "green" they see is the same as the "green" their friend sees can attest to this — the researchers only tested whether the mice could discriminate among the lights.

"Each photoreceptor absorbs a range of wavelengths, but the efficiency changes with wavelength," Nathans explains. "For example, one photoreceptor might absorb green light only half as efficiently as red light. If an animal had only this type of photoreceptor, then a green light that was twice as bright as a red light would look identical to the red one. But if the animal adds a second photoreceptor with different absorption properties, then by comparing both receptors, the red and green lights could always be distinguished."

Normal mice failed to discriminate yellow versus red lights when the light intensities were set to give equal activation of their middle wavelength receptor. However, mice with both the human long wavelength and the mouse middle wavelength receptors learned to tell the difference, although it took over 10,000 trials to learn to make the distinction.

Nathans suggests that these knock-in mice mimic how our earliest primate ancestors acquired trichromatic vision, color vision based on three receptors. At some point in the past, random mutations created a variant of one receptor gene, located on the X chromosome, producing two different receptor types. Present-day New World (South American) monkeys still use this system, which means that in these monkeys only certain females can acquire trichromatic color vision.

In contrast, among Old World (African) primates such as humans, the two different X chromosome genes duplicated so that each X chromosome now carries the genes for both receptor types, giving both males and females trichromatic color vision.

"You could say that the original primate color vision system, and the one that New World monkeys still use today, is the poor man's — or to be accurate, poor woman's — version of color vision," Nathans says.

Johns Hopkins Medical Institutions