It takes an army of neurons to move a person's legs. But events that set the stage for one's ability to walk occur early in development when many thousands of neurons are gathered into the five columns located within the spinal cord. Those…
It takes an army of neurons to move a person's legs. But events that set the stage for one's ability to walk occur early in development when many thousands of neurons are gathered into the five columns located within the spinal cord. Those motor neurons are then further grouped into about 200 pools of neurons that connect to specific targets in limb muscles or other cells. Jeremy Dasen at New York University Medical Center is deciphering the molecular code that helps developing motor neurons in the spinal cord connect with the muscles that they control. These neurons make contact with a large variety muscles in each leg and arm, and these fragile connections make tasks, such as walking or reaching, possible. As a postdoctoral fellow in HHMI investigator Thomas Jessell's lab at Columbia University, Dasen discovered that this code is written in the language of Hox proteins—a family of transcription factors (proteins that activate specific sets of genes) found in virtually all organisms. Scientists have long recognized that Hox proteins, by orchestrating a cascade of gene expression in the early embryo, ensure animals' overall body plan. They place the head at the top, the feet below, and the correct arrangement of ribs in between. Dasen and his colleagues at Columbia found that Hox proteins also influence the arrangement of the motor neuron columns within the spinal cord. Understanding the code may help scientists restore motor neuron function in people whose spinal cord has been damaged by trauma or disease. Dasen is now exploring whether Hox proteins help assemble the complete circuits that control walking and running. Dasen is focused on determining the function of the proteins produced by the two dozen Hox genes found in the spine. He is specifically looking at how the proteins produced by Hox genes act as master gene regulators within motor neurons and how they help in the formation of synapses, the communication junctions between neurons and muscles. "I've always been interested in the problem of how genes control development," says Dasen. "One of the most interesting contexts is the nervous system. We're trying to understand the logic of how neural circuits are assembled in the spinal cord and whether Hox genes are critical determinants in the shaping of locomotor and other vital behaviors." Dasen uses mouse and chick models to make genetically modified cells without Hox genes to better understand which "downstream" genes—those down the molecular signaling pathway from Hox genes—are affected in the building of a synapse. "We can create mice where one or a number of Hoxgenes are mutated in just the motor neurons, or just in other kinds of neurons, and then make observations," he says. "We ultimately want to understand how manipulating connections in the circuit influences the physiology and behavior of the animal—how the system is wired up and what it means in terms of motor function." The Hox genes Dasen is studying have a known function in motor neurons, but their functions in sensory neurons and interneurons are largely unknown. "We're asking what happens when we delete Hox from just the sensory neurons," he continues. "As a result, does that sensory neuron form a synapse with an inappropriate motor neuron? Does it really need the Hox genes? We're trying to delineate the basic idea that there is a molecular logic going on here." He is also exploring the relationship between Hox genes and other proteins, such as Fox P1, a protein found only in the motor neurons that move the legs. "We'd like to get to the root of relationships like these to better understand exactly how vital Hox genes are in locomotion," Dasen says.