Researchers are untangling how a protein helps point motor neurons toward their correct destinations.

A cross section of an embryonic spinal cord, with clusters of FoxP1 labeled in red.

Every movement, from picking up a pencil to doing a backflip, requires the precise wiring of specific neurons in the body. If a motor neuron destined for the leg instead wound its way along an arm during development, chaos would ensue.

“Mammalian limbs possess over 50 muscle groups and each is innervated by its own, dedicated, set of motor neurons,” says HHMI investigator Thomas M. Jessell, whose lab at Columbia University has studied a key gene for controlling that specificity.

The Jessell lab had already found that the Hox family of genes plays a role in determining which neurons go where. But there are 21 Hox genes involved in mice neuron development, and so probing their function further by gene inactivation would be a laborious task. Jessell and his colleagues searched for factors that might be required for Hox activity and discovered that the transcription factor FoxP1 is needed for the activity of all 21 Hox proteins, permitting a way of inactivating all Hox proteins involved in spinal motor neuron differentiation. “FoxP1 gives us access to the entire Hox program at one fell swoop,” says Jessell.

The team looked in mice with mutated FoxP1 to see whether motor neurons would simply stall at the base of a limb. Instead, they observed the axons of motor neurons projecting along random paths in the limb.

“It's as if you're blindfolded in a garden maze and told to keep moving,” Jessell says. “You'll take any of the paths that are available to you, but you'll just be wandering aimlessly.”

This randomness is a disaster for motor control, he says. In effect, the mice with the mutation have a spinal motor system that resembles those found in more primitive vertebrates. The results are published in the July 25, 2008, issue of Cell.

Mice with a complete loss of FoxP1 activity die before they're born, so Jessell and his colleagues are now developing ways to eliminate the protein solely from motor neurons. They hope to elucidate the biochemical and functional connection between FoxP1 and the Hox proteins.

Image: Jeremy Dasen / Jessell lab