A protein interaction that helps guide cells from the eye to a tiny midbrain processing hub during brain development has been identified by researchers.
Nestled deep in the middle of the vertebrate brain is a multi-sensory integration and movement control center called the superior colliculus. In rodents, this brain region integrates multi-sensory inputs - visual cues, sounds, touch information, and smells - and delivers output signals to a variety of motor control centers in the brain, coordinating the animal's movements in response to its environment.
Although the superior colliculus composes a relatively small portion of the brain's volume in mice, it's a processing powerhouse - in part, because it's formed by precise cellular layers that organize and refine signaling patterns.
"This brain region is interesting because it integrates data from multiple sensory inputs, helps form a binocular image of the world, and then dictates the animal's innate behaviors - such as running away from a predator or hunting prey - based on those data," said Fox, who is also the director of the Virginia Tech College of Science's School of Neuroscience.
During early brain development - weeks before a mouse opens its eyes for the first time -neurons extend long axonal processes from back of the eye, forming the optic nerve. These growing cells eventually branch off to shape thousands of intricate connections in precise brain regions, including the superior colliculus.
How these cells know where to migrate largely remains a mystery, Fox says. But understanding this key phase of development could potentially provide new information that could help researchers in future studies identify ways to regenerate injured optic nerve fibers.
"If our goal is to one day regenerate damaged brain circuits to restore vision, then first we need to know how to get the cell's axons to grow into a precise destination in the brain," Fox said.
Fox and his team examined how a specific subtype of optic nerve cells - ipsilateral retinal ganglion cells - finds its way to the superior colliculus during brain development.
The researchers used a virus to identify which types of neurons the retinal ganglion cells made connections with once inside the superior colliculus. This led them to identify two proteins that chaperone this circuit formation.
One protein, emitted by a type of excitatory neuron in the superior colliculus, lures the optic nerve cell closer like a molecular homing beacon. Once the migrating cell is in the right place, this protein docks into a perfectly fitted receptor protein located on the nerve cell's membrane. This chemical reaction tells the cell it's reached its destination.
When the beacon molecule - called nephronectin - is absent, a visual layer of the superior colliculus doesn't form properly, and the mice have trouble hunting prey.
The mouse superior colliculus has been studied extensively for more than 60 years. Though it's present in all mammalian species, in humans this brain region takes up less relative volume and is thought to play a role in stabilizing our image of a moving world by controlling head, neck, and eye movements.
Fox says this study represents an early research collaboration between Children's National Hospital and the Fralin Biomedical Research Institute researchers. He recalls when Virginia Tech's Vice President for Health Sciences and Technology Michael Friedlander connected Fox and Jason Triplett, a principal investigator at Children's National Hospital in Washington, D.C., seven years ago.
"We talked about studying how these neurons project to the colliculus back in 2013, and we've since worked on numerous grant-funded projects together," Fox said. "This paper was born from those early discussions."
The study's co-first authors worked in Fox's lab at the Fralin Biomedical Research Institute: Jimmy Su, a research assistant professor, and Ubadah Sabbagh, a former graduate research assistant during the time of the study, who is now a postdoctoral researcher at MIT.
Other research contributors include Yuchin Albert Pan, an associate professor at the Fralin Biomedical Research Institute; Yanping Liang, a research assistant at the Fralin Biomedical Research Institute; Lucie Olejnikova, a former postdoctoral researcher at the Fralin Biomedical Research Institute; Karen Dixon, a research technician in Triplett's lab; Ashley Russell, a former postdoctoral research fellow at Children's National Hospital; and Jiang Chen, a former postdoctoral research at the Fralin Biomedical Research Institute.
This research was supported in part by the National Eye Institute.